Farnesyltransferase Inhibitors

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Farnesyltransferase Inhibitors: A Comprehensive Review Based on Quantitative Structural Analysis N.S.H.N. Moorthy*, S.F. Sousa, M.J. Ramos and P.A. Fernandes REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, s/n, Rua do Campo Alegre, 4169-007 Porto, Portugal Abstract: Farnesyltransferase inhibitors (FTIs) have mainly been used in cancer therapy. However, more recently, investigations on these inhibitors revealed that FTIs can be used for the treatment of other diseases such as Progeria, P. falciparum resistant malaria, Trypnosomatid, etc. Hence the development of novel FTIs is an important task for the drug discovery program. Initially, numerous peptidomimetic FTIs were developed from the template of CAAX (CVIM was the first pharmacophore model used as a peptidomimetic). Later, many non-peptidomimetic FTIs have been discovered with the structural modification of the peptidomimetics. The structural analysis of those developed FTIs by various researchers suggested that the presence of a heterocycle or a polar group in place of the thiol group is required for interaction with the Zn2+ ion. The bulky naphthyl, quinolinyl, phenyl, phenothazine, etc in this position provide better hydrophobicity to the molecules which interact with the aromatic amino acid moieties in the hydrophobic pocket. A hydrophilic region with polar groups is necessary for the polar or hydrogen bonding interactions with the amino acids or water molecules in the active site. Many FTIs have been isolated from natural products, which possessed inhibitory activity against farnesyltransferase (FTase). Among them, pepticinnamin E (9R), fusidienol (9T), gliotoxin (9V), cylindrol A (9X), etc possessed potential FTase inhibitory activities and their structural features are comparable to those of the synthetic molecules. The clinical studies progressing on FTIs showed that tipifarnib in combination with bortezomib is used for the treatment of patients with advanced acute leukemias. Successful phase I and II studies are undergoing for tipifarnib alone or in combination with other drugs/radiation for the treatment of multiple myeloma, AML, breast cancer, mantle cell lymphoma, solid tumors, non-small cell lung cancer (NSCLC), pancreatic cancer, glioblastoma, etc. Phase I pharmacokinetic (maximum tolerated dose, toxicity) and pharmacodynamic studies of AZD3409 (an orally active double prodrug) is progressing on patients with solid malignancies taking 500 mg once a day. A phase II study is undergoing on lonafarnib alone and in combination with zoledronic acid and pravastatin for the treatment of Hutchinson-Gilford Progeria syndrome (HGPS) and progeroid laminopathies. Lonafarnib therapy improved cardiovascular status of children with HGPS, by improved peripheral arterial stiffness, bone structure and audiological status in the patients. Other important FTIs such as BMS-214662, LB42908, LB42708, etc are under clinical studies for the treatment of various cancers. This review concluded that the quantitative structural analysis report with an elaborative study on the natural product compounds provides ideas for development of novel molecules for the FTase inhibitory activity. The fragment based analysis is also needed to select the substituents, which provides significant inhibitory activities and can also have good pharmacokinetic properties in the clinical studies.

Keywords: Anticancer, farnesyltransferase inhibitors, natural products, QSAR, tipifarnib, lonafarnib. INTRODUCTION Over the past years, farnesyltransferase (FTase) has become a major target in the development of potential anticancer drugs [1]. Recently, several research groups worldwide have suggested that farnesyltransferase could be an effective target for drug development against Progeria and parasites diseases such as P. falciparum resistant malaria, trypanosomatid infections (African sleeping sickness), Chagas disease, Toxoplasmosis and Leishmaniasis and as antiviral agents [210]. FTase is one of three prenyltransferase enzymes used by normal and malignant cells to catalyze covalent attachment *Address correspondence to this author at the REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, s/n, Rua do Campo Alegre, 4169-007 Porto, Portugal; Tel: +351-220 402 506; E-mail: [email protected], [email protected] 0929-8673/13 $58.00+.00

of prenyl groups to >300 polypeptides in the human proteome [11, 12]. The prenyltransferases are a family of zinc metalloenzymes that catalyze the prenylation (addition of a prenyl group through a thioether linkage) of a particular set of proteins, which has crucial effect on the transduction pathway. There are three members of the prenyltransferase family: farnesyltransferase (FTase), geranylgeranyltransferase-I (GGTase-I), and geranylgeranyltransferase-II (GGTase-II). Both FTase and GGTase-I are heterodimeric proteins that share a common -subunit and have similar protein substrate requirements [13]. GGTase-II transfers two geranylgeranyl groups to protein trafficking Rab proteins that contain Cys-Cys or Cys-Ala-Cys sequences at the Cterminus [14]. Mammalian FTase is a heterodimeric zinc metalloenzyme composed of 48 kDa -subunit and 46 kDa -subunit © 2013 Bentham Science Publishers

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that catalyses the transfer of a farnesyl group (a 15-carbon isoprenoid lipid moiety) from farnesyl pyrophosphate (FPP) to the thiol of a cysteine (Cys) residue near the carboxy terminus of more than 60 signal transduction proteins in the eukaryotic cell, including members of the Rho and Ras superfamily of G proteins [15, 16]. The key C-terminal sequence recognised by FTase is a CAAX tetrapeptide sequence (“C” refers to the cysteine, “A” to any aliphatic amino acid often methionine, and “X” to any amino acid glutamine or serine in FTase and leucine or phenylalanine in GGTase-1) [16]. GGTase-1 transfers a 20-carbon geranylgeranyl moiety to the -subunits of heterotrimeric G-proteins [17]. Ras is synthesized in the cytoplasm as a biologically inactive cytosolic propeptide (Pro-Ras) and undergoes a series of closely linked post-translational modifications by the covalent addition of a non-polar farnesyl group (C15 farnesyl isoprenoid (FI)) to the COOH-terminal of the CAAX, leading to increased hydrophobicity. The Zn2+ ion present in the FTase enzyme is not necessary for FPP binding but it is required for CAAX protein coordination. In addition, this enzyme also requires Mg2+ for maximal levels of activity, although this metal is present only in millimolar (mM) concentrations [18]. The role of Mg2+ has not been yet clearly defined, but several lines of evidence support the idea that Mg2+ plays an important role in the stabilization of the pyrophosphate leaving group [18, 19]. The post-translation modifications are the farnesylation of C-186 by the cleavage of the three downstream amino acids (AAX), followed by methylation of C-186 and, finally, a palmitoylation of cysteine residues in the region 165-186 (Fig. 1). Cysteine mutation in the CAAX box prevents farnesylation and Ras function [20]. K-Ras and N-Ras (the Ras isoforms commonly mutated in cancer) undergo alternative prenylation by a related enzyme, GGTase-I, when FTase activity is inhibited by FTIs. The catalytic reaction is the same as the FTase’s, but adds the more hydrophobic C20 geranylgeranyl isoprenoid (GGI) to the cysteine residue of the CAAX motif. However, unlike FTase, the related enzyme GGTase-I does not require magnesium for optimal activity [18, 19, 21]. In a crystal structure of FTase and FPP, the isoprenoid is bound in an extended conformation at the hydrophobic cavity of the -subunit [22]. The substrates for prenyltransferase family enzymes such as FPP and geranylgeranyl pyrophosphate (GGPP) compete to bind FTase with high affinity, but the size of the aromatic pocket can only accommodate FPP [23, 24]. Earlier studies explained that FPP is the first substrate to bind FTase [25] and that it leaves the metal coordination sphere unchanged. Consequently, the CAAX protein substrate binds [25], with the CAAX cysteine sulphur atom directly coordinating Zn2+ ion [26] and locking the Asp297  residue into the monodentate state [27]. Experimental evidences [26, 28] and theoretical results [27] suggest that the cysteine residue initially coordinates the metal atom as a thiol, and subsequently loses the proton to a base in the active site to form a more stable Zn2+-bound thiolate. Two reactive atoms such as the Cl atom of FPP and the Zn2+ bound cysteine’s sulphur are left with something like 8 Å away [2931], a distance that must be reduced for the reaction to take place. The FPP substrate then suffers a major rearrangement through a rotation of the first two isoprenoid subunits (i.e.

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from C1 to C10) [1, 32, 33], bringing the two reactive atoms to a distance of around 5-5.5 Å at which the chemical step can take place [18, 19, 34]. FTASE INHIBITORS (FTIs) FTIs have been extensively developed as anticancer agents because of their ability to block tumor growth in experimental animals [35]. The inhibition of the prenylation of Ras and Rho proteins is the mechanism of action of FTIs, as K-Ras can suffer alternative prenlyation by GGTase-I (when FTase is inhibited) in cancer therapy. Ras proteins have been implicated in something like 30% of all human cancers. Examples include pancreatic adenocarcinomas (90%), colon adenocarcinomas and adenomas (50%), lung adenocarcinomas (30%), myeloid leukemias (30%) and melanomas (20%) [36-40]. As per the literature, the FTase inhibitors have been shown to possess antimalarial activity in addition to anticancer activity. In fact, the genome sequence data of P. falciparum has indicated the absence of GGTase-1 in the parasite [41]. This has led to the investigation of P. falciparum PFT (PfePFT) as potential target for the development of new antimalarials [16, 42-48]. Nallan et al. have evaluated different mammalian cell-optimized FTIs as new class of antimalarials against PfePFT [49] and anti-trypanosome agents. These compounds are much more toxic to these parasites than to the mammalian cells, and there are a large number of lead compounds (Bristol-Myers Squibb’s (BMS) tetrahydroquinoline (THQ) prototypes were adopted) from which an antiparasite drug discovery program to be launched [10, 17, 33, 50, 51]. Recent clinical studies show that FTIs can be used for the treatment of Progeria, which is also known as HutchinsonGilford Progeria Syndrome (HGPS), a rare, fatal genetic disease characterized by an appearance of accelerated aging in children and originally described by Hutchinson in 1886 [52]. It is caused by de novo dominant mutations in lamin A. Lamin A is synthesized as a precursor, prelamin A, which has a CAAX motif at its carboxyl terminus. The CAAX motif signals a series of catalytic reactions resulting in a carboxyl-terminal cysteine that is farnesylated and carboxymethylated [53, 54]. Progerin toxicity is attributed at least in part to its farnesyl moiety, as chemical inhibitors of FTase reverse abnormalities in nuclear morphology in progerin expressing cells [53, 54]. The reported literature explained that the FTIs used for the treatment of various cancer, parasitic diseases, Progeria, etc. So it is important to develop novel molecules with less or free of toxicity and good activity on the target. Hence, in this review we have discussing the chemical features of the FTIs needed for activity elucidation and the molecules in the clinical studies against different targets. HISTORY OF FTIs DEVELOPMENT The development of FTIs was initiated by the observation that in 30% of all human cancers occurred by the mutated forms of Ras proteins [36-40, 55]. The C terminal CVIM-tetrapeptide of K-Ras was a starting point for the development of a pharmacophore model for the FTIs discovery and the CVIM fragment served as an alternative substrate for FTase (less active after S-farnesylation). These discoveries

Structural Analysis of FTase Inhibitors

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Fig. (1). Schematic representation of mechanism of action of FTase (A) and GGTase-1 (B) enzymes.

suggest that true non-substrate FTIs are obtained from Nacylation of the amino terminus (cysteine) of the tetrapeptide [56-59]. Reduction of two amide functional groups to amines and incorporation of an aromatic side chain into the AA residue (AA residue in CAAX) leads to the formation of CVFM peptide mimetic [59, 60]. CVFM gave 50% inhibition at a concentration of 25 nM, which is 6-fold lower than that of the natural sequence, CVIM. First generation CVIM peptidomimetics were developed with the replacement of the dipeptide `VI' with aminomethylbenzoic acid (AMBA) [55, 59-62]. The tetrapeptide non-substrate inhibitors were developed by the modification of aromatic residue at the terminal A position. This aroused interest into developing low molecular weight CAAX peptidomimetics for FTase inhibition [56, 63-65]. The tetrapeptide mimetic Cys-AMBA-Met (IC50 = 0-10 M), where the AMBA substituted for "VV," "II," and "VI" in CVVM, CIIM, and CVIM inhibited COLO-205 and Daudi p21ras FTase in a dose-dependent manner with IC50 values of 60 and 120 nM respectively [61, 62, 66-68] (Fig. 2). The second generation prenyltransferase inhibitors are called dual prenyltransferase inhibitors (DPTI) and have inhibitory activity against FTase and GGTase enzymes. AZD3409, is a second generation drug which completely inhibits prenylation of Ki4B-Ras, resulting an increased antitumor effect [36, 69, 70] (Fig. 3). FTI-276 (CAAM) is a third generation peptidomimetic (peptidomimetic of the COOH terminal Cys-Val-Ile-Met of K-Ras) where `VI' was replaced by 2-phenyl-4aminobenzoic acid [71]. It possessed potential FTase (IC50 = 0.5 nM) and GGTase-I inhibitory activities (IC50 = 50 nM). FTI-277 is also a third generation molecule that blocks the constitutive activation of MAPK in H-RasF, but not HRasGG or Raf-transformed cell at higher concentration. GGTI-297 (CAAL) is also an analog of FTI-276, which inhibits selectively GGTase-I (IC50 = 55 nM) over FTase (IC50 = 203 nM) [71-75] (Fig. 4). These peptidomimetic FTIs have potent in vitro activity, but possessed several undesirable peptide features that affect its in vivo efficacy. These features have led to the generation of the first non-peptide mimetic of CAAX (replacement of tripeptide AAX by biphenyl derivatives) (compounds 1-3 in Fig. 3) (replacement of VIM in CVIM by non-peptide) (these are also some second generation FTIs). These inhibitors exhibit potent in vitro selective inhibitory activity against the FTase enzyme (IC50 = 50-150 nM) [57, 61, 76, 77] (Fig. 3).

The next generation FTIs started with the replacement of the thiol groups with other heterocycles. FTI-2148 is a derivative of FTI-276, where the cysteinyl residue and the phenyl groups are replaced by an imidazole derivative and a tolyl group, respectively [75]. The most frequently used replacements for cysteine are nitrogen-containing heterocycles. Similar strategies were used to design CVLL peptidomimetics such as GGTI-298 and GGTI-2154 as GGTase-I inhibitors [72, 75]. This non-thiol (FTI-2148) is highly selective for FTase (IC50 = 1.4 nM) over GGTase-I (IC50 = 1700 nM), where as GGTI-2154 displays reverse selectivity (GGTase-I and FTase have IC50 = 21 and 5600 nm respectively). The molecule (prodrug) FTI-2153 has action on H-Ras rather than Rap1A, while GGTI-2166 is selective for Rap1A [7581] (Fig. 5). Recently, Qiao et al., have developed a new type of peptidomimetic compounds, which are characterized and found to be dual protein inhibitors for both FTase and GGTase-I. These compounds have similar chemical and physical properties to -CAAX motif of the protein substrate, which may facilitate their transfer to appropriate drug targets in vivo [82]. FTI design has evolved from early thiol containing peptidomimetics to recent non-thiol, non-peptidic, and imidazolecontaining chemical entities [83-85]. This leads to the development of novel FTIs for cancer therapy, which are in clinical trials. The presence of the thiol or non-thiol (heterocycles) functional groups plays important roles in the observed interactions. The ring nitrogen atom (in imidazole and/or other heterocycles) is supposed to coordinate to the enzymebound Zn2+ ion, similarly to the cysteine thiol group [85-89]. Nitrogen heterocycles can be replaced by aryl residues lacking the ability to coordinate metal atoms, without losing too much of their FTase inhibitory activity [86-90] (Fig. 6). More importantly, free thiols are a source of adverse drug effects as it happens with the angiotensin converting enzyme inhibitor captopril. Therefore, current development is clearly directed towards the so called non-thiol FTIs [91]. Many non-thiol FTIs developed by the replacement of the cysteinyl residue by phenol (IC50 = 22 M) [92, 93], lactam (IC50 = 10 M) [92] or carboxyl (IC50 = 120 M) [92, 94] moieties attained limited success. Another drawback associated with the replacement of the thiol by other functional groups is the loss of a significant portion of the binding energy. This can be overcome by the addition of a lipophilic moiety to the terminal moiety of the CAAX-peptidomimetic, which presumably

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Fig. (2). FTIs-First generation.

Fig. (3). FTIs-Second generation.

occupies considerable portions of the hydrophobic region in the FTase active site, resulting in a regain of at least some of its lost affinity. The additional hydrophobic interactions would enhance the overall binding energy [92, 95]. Hence, some FTIs have been developed with the presence of bulky substituents such as phenothiazine, quinolines, naphthyl, etc,

which improve the FTase inhibitory activity of the molecules by binding in the hydrophobic binding site of the enzyme. The phenothiazine and ferrocene (a well-tolerated bulky group) units in the molecules make the hydrophobic interaction and the chelating action (with the Zn2+ ion) in the active site of the FTase (Fig. 6) [96-98].

Structural Analysis of FTase Inhibitors

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Fig. (4). FTIs-Third generation.

Fig. (5). FTIs-Next generation (non-peptide).

Recently, many FTIs have been developed with improved FTase inhibitory activity, pharmacokinetic profiles and reduced toxicity. In order to improve the pharmacokinetic properties of the molecules, Driggers et al., have suggested making macrocycles of the linear molecules. Some of the FTIs developed by this concept improved the pharmacokinetic properties and reduced the cardiotoxicity. These macrocycles can serve as a domain that modulates physicochemical, pharmacokinetic and even biological properties [99-101]. A graphical representation of the history of FTIs development is provided in (Fig. 7). In addition, the potential effect of FTIs for the treatment of cancer and other diseases, the combination of FTIs with other cancer therapeutic agents including taxanes [102, 103], cisplatin [104-106], tamoxifen [107-109], 5-fluorouracil [110, 111], cyclin-dependentkinase (CDK) inhibitors [112], MEK kinase inhibitors [113], and gemcitabine [104, 114-116], and in radiation combination studies [117, 118] improve their efficacy [19, 119]. STRUCTURE ACTIVITY RELATIONSHIP (SAR) AND QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP (QSAR) STUDIES ON FTIs The structure activity relationship analyses of the existing compounds is important to develop novel moieties with

pharmacodynamic and pharmacokinetic compatibility. Venet et al., [120] proposed that the imidazole N-3 of the tipifarnib is coordinated to the Zn2+ ion present in the active site of the protein. This hypothesis has been reinforced by the fact that hindered N-imidazoles (presence of bulky substituents in the position) are found to be inactive. Following the replacement of the imidazole by pyridyl, it has found that only 3-pyridyl substituent possessed significant FTase inhibitory activity. The geometrical isomerism of the active compound tipifarnib explained that the R enantiomer proved to be about 50 times more potent than the S isomer. In order to reduce or eliminate the cytochrome P450 inhibition by the tipifarnib, modifications on the imidazole ring of the molecules is appropriate [119-122]. Wang et al., [85] has developed some cyano imidazolyl derivatives and investigated the comparative binding features analysis with tipifarnib. They explained that the 5-cyano-2-pyridyl group present in A315493 occupies the same site as the N-methylquinolin-2-one of tipifarnib. The cyano group next to the 1-naphthyl of A315493 and the 4-chlorophenyl group of tipifarnib orient towards the same region in the active site of the FTase enzyme, but bind differently in the active site [85]. Several studies reported in the literature explained the SAR of a large variety of FTIs [24, 55, 59, 92]. Hence in this review, we have explained elaborately the structure activity relationship and the binding features of FTIs for the FTase inhibitory activity with the help of the QSAR and other computational related techniques (Table 1). QSAR AND RELATED COMPUTATIONAL STUDIES ON FTIs One of the major goals of a drug design strategy is the identification of leads from large databases or libraries and optimization of the lead as per need. Computational approaches based on discrimination functions are used to classify active compounds from inactive ones and to predict the biological activity of new lead compounds. The cheminformatical in silico methods along with other structure-based

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Fig. (6). FTIs-Non-thiol and non-peptide derivatives.

Fig. (7). Graphical representation of the history of the FTIs.

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Structural Analysis of FTase Inhibitors

Table 1.

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Summary of the Computational Work Reported on FTIs

S. No

Chemical Name

Type of Analysis

Reference No

1

Benzonitrile derivatives

CoMFA

[85, 129]

2

Structurally different compounds with imidazole, benzimidazole and benzonitrile groups

CoMFA and CoMSIA

[121, 122, 130, 131]

3

Abbott-initiated imidazole-containing compounds

Docking, CoMFA and CoMSIA

[85, 121, 122, 131, 132]

4

Structurally different compounds (ether and 2-aminonicotinonitrile derivatives)

3D-QSAR, MFA

[14, 133, 134]

5

Non-thiol CAAX peptidommetic inhibitors

Genetic neural network

[135, 138, 139]

6

Structurally diverse compounds (imidazole and other nucleus)

Pharmacophore analysis

[85, 121, 122, 132, 133, 140]

7

Piperidine derivatives

QSAR-MLRA

[21, 141]

8

Benzofuran derivatives

QSAR-MLRA

[142, 143]

9

SCH 226734, R115777, SCH 66336, BMS 214662, L-778123 and U49

MD, DFT, virtual screening. ADMET

[144-147]

10

Piperidine substituted trihalobenzocyclohepta pyridine analogues

MLRA

[148-151]

11

Cinnamaldehyde analogues

3D-QSAR-PLS

[152, 153]

12

2,3-Bis-benzylidenesuccinaldehyde derivatives

CoMFA and CoMSIA

[154]

13

Large, diverse data set

Neural network & MLRA

[149]

14

1-(4-Pyridylacetyl)- 4-(8-chloro-5,6-dihydro-11Hbenzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine derivatives

Pharmacophore model

[157-161]

15

Benzo[f]perhydroisoindole

Response surface modelling QSAR

[162]

16

2,5-Diaminobenzophenone

CoMFA and CoMSIA

[163]

17

Imidazole containing 2,3,4,5-tetrahydro-1Hbenzo[c][1,2]diazepines

QSAR-MLRA

[164]

18

Imidazole containing 2,3,4,5-tetrahydro-1Hbenzo[c][1,2]diazepines

QSAR-MLRA, ANN, SVM

[165]

19

Aryl thiophene derivatives

QSAR-MLRA

[166, 167]

20

6-Cyano-1-(3-methyl-3H-imidazol-4-yl methyl)-3-substituted1,2,3,4-tetrahydroquinoline derivatives

QSAR-MLRA

[17, 49, 168, 169]

21

Cinnamic acid derivatives

CoMFA and CoMSIA

[2, 43, 132, 170-175]

22

2,5-Diaminobenzophenone

MIA-QSAR

[176]

23

1,2,3,4-Tetrahydroquinoline and benzonitrile analogs

Multivariate image analysis QSAR

[17, 129, 177]

approaches appear to be particularly rewarding in terms of both cost and time benefits [123-127]. Computational studies on the FTIs are undergoing in our laboratory especially involving the characterization of the FTase active site and the design of novel FTIs [1, 18, 19, 27, 34, 128]. In this section we are reviewing the QSAR and related computational analysis performed on FTIs. 1.

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Puntambekar et al., [129] have reported a comparative molecular field analysis (CoMFA) on a set of benzonitrile derivatives as FTIs. The authors explained the CoMFA results as an indicative of the importance of

steric bulkiness and electrostatic potential for the inhibitory activity. The results showed that positively, negatively charged groups and the aryl groups substituted on ring A are favoured for the FTase inhibitory activity. The electronegative substituents in ring A especially Cl or CN in para positions and Cl or F in meta position are observed in most of the compounds for favourable activity. The less active compound in the series possess NH2 group at para position. Bulky aryl groups attached to ring A (ring C), have shown better inhibitory activity, while steric bulkiness vicinity of the cyano group at-

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tached to ring A is unfavourable, which suggested that the bulkier substituents on ring A are detrimental for FTase inhibitory activity. These results described the importance of steric bulkiness and electrostatic potential of these compounds for FTase inhibitory activity [85, 129] (Fig. 8A). 2.

A group of researchers reported CoMFA and comparative molecular similarity analysis (CoMSIA) of 46 FTIs containing an imidazole and benzonitrile groups as structural key elements and discussed the features needed for the inhibitory activity. The CoMFA analysis revealed that the electropositive group at the para position of the phenyl ring connected to N3 imidazole is favourable for the interaction with negative charged groups in the active site. The positive charge around the imidazole ring is mandatory for the FTase inhibitory activity. As per their view, the result of 3D-QSAR, CoMFA and CoMSIA obtained from pharmacophore based alignments (CoMFA and CoMSIA) are complimentary to each other.

The alignment results suggest that the distance between N1 of the imidazole ring of the active compound and the Zn2+ ion was 2.71 Å. The group substituted in the 4th position of the imidazole ring is sterically preferred such as indole, which oriented towards the hydrophobic pocket (Tyr361 and Trp106) in the active site, but too bulky groups are unfavourable. The positive charge of the molecules mainly caused by the nitrogen atoms and changes in the electronwithdrawing groups at the para position of the phenyl ring are sensitive to activity. The CoMSIA also revealed that the linker between phenyl and imidazole rings represent an area where no substitution is favoured. A strong electron withdrawing group (cyano) makes phenyl rings positive, hence these are electron deficient. The electron rich substitution at ortho position is favourable for inhibitory activity. The combination of these CoMFA, CoMSIA and docking results provided important informations that the imidazole and the para substituted phenyl ring is favourable for the activity. Meanwhile, other groups attached to the N3 position of the imidazole are important for the electron positive environment of the imidazole ring, which can orient towards the negative charged area in the active site [121, 122, 130, 131] (Fig. 8B). 3.

3D-QSAR (CoMFA and CoMSIA) and docking studies are reported on a highly diverse series of 192 Abbottinitiated imidazole-containing compounds [85, 121, 122, 131-133]. The combined CoMFA/CoMSIA models provided a better model than the corresponding CoMSIA models. The selected model with r2 = 0.878, q2 = 0.630 and r2pred = 0.614, provides explicit indication for lead optimization regarding steric, electrostatic, hydrophobic, and H-bond accepting properties, and is in agreement with the pockets of the active site (composed of a group of hydrophobic amino acids including Tyr93, Leu96, Trp102, Leu103, Trp106, Phe360, and Tyr361), and exposed to the solvent. The docking analysis showed that the compound (3-Cl in C ring and CH3SO2 in D ring) did not provide good affinity with the FTase active site due to the steric hindrance of the relatively bulky (methylsulfonyl) group in the para position of ring ‘‘D’’ and in other compound, the benzodioxazole ring in ortho po-

sition forced ring ‘‘C’’ to come out of the active site. The presence of a bulky ring (naphthyl) and no ring in the C position were unfavourable for the inhibitory activity. In this case, the presence of a cyano group in the A ring pointed into the spacious active region (where the C ring binds). If no ring was present in the C position, due to less steric effect on the A ring, the latter oriented towards the imidazole binding deep pocket area [85, 121, 122, 131-133] (Fig. 8C). 4.

Eqbal et al., [134] have reported 3D–QSAR analysis on a set of hundred ether analogues employing the molecular field analysis (MFA) technique. They reported that the steric (CH3) and the electrostatic (H+) interaction of the molecules play an important role in the inhibition of FTase by ether analogues. The results explained the appearance of a steric descriptor (CH3/1319) and (CH3/999) on the CH2COCH3 group of the C ring with positive coefficient and the presence of CH3/1165 with negative coefficient (in the receptor site), indicating that moderately bulky substituents would be favourable. The presence of (H+/1142) with a positive coefficient (in ring A) indicates that an electron withdrawing group at the meta position of ring ‘A’ is favourable for the activity. The presence of (H+/1465) with positive coefficient indicates that an electron withdrawing group increases the activity at the meta position of ring ‘B’; hence, molecules possessing a fluorine substituent showed higher activity as compared to molecules with less electronegative properties. The authors concluded that the substitution in ring A (meta or para) is important for the inhibitory activity [14, 133, 134] (Fig. 8D).

5.

A set of 78 CAAX peptidommetic inhibitors including 32 thiols and 46 non-thiols possessing inhibitory activity on the FTase enzyme was analysed by a genetic neural network (GNN) approach [135], using radial distribution function (RDF) descriptors. The RDF approach has been introduced by Gasteiger et al., [136] in order to evaluate the correlation between structure and activity (this theoretical approach is successfully applied for deriving the 3D structure of organic molecules from their infrared (IR) spectra). RDF descriptors in linear model multiple regression analysis (MRA) have been developed between the inhibitory activity and the 3D molecular distribution of mass, van der Waals (vdW) volume, polarizability and electronegativity calculated at radii ranging between 4.0 and 15.0 Å from the geometrical center of each molecule. They have observed that the main difference was on the mass distribution in the outer parts of the molecule, specifically at radii ranging from 12.0 to 14.0 Å. They have compared also the results with the reported docking study of non-thiol FTIs. The ability of the hydrophobic outsider substituents of the inhibitor properly matching into a complex multi-binding pocket is the main interaction governing its inhibitory efficiency [135, 137-139] (Fig. 8E).

6.

A diverse set of 203 compounds (22 training and 181 test set) (IC50 values ranges between 0.014 and 1800 nM) were used for the pharmacophore analysis [140]. The best pharmacophore hypothesis (one hydrogenbond acceptor (HBA), one hydrophobic point (HY), and

Structural Analysis of FTase Inhibitors

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8A

8B

8C

9

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8E

8D two ring aromatics (RA)), has a correlation coefficient of 0.961, a root mean square deviation (RMSD) of 0.885, and a cost difference of 62.436. This model provided some false positive and negative results on the activity prediction. The most active compound in the test set and over all the data set had fitness scores of 11.05 and 12.39 respectively. The model was validated by spiked database (D) with 1525 compounds and the least active compound had a fitness score of 8.46. The HBA feature corresponds to CN at C4 of the phenyl ring attached to the imidazole ring (comp 1), and the hydrophobicity of the phenyl rings (RA1 and RA2) are favourable for the inhibitory activity [85, 121, 122, 132, 133, 140] (Fig. 8F). 7.

In a research paper, the authors have developed some piperidine derivatives with FTase inhibitory activity and reduced glucouronide potential. Various substitutions and exchange of the phenyl group at the C-2 position of the 2-(4-hydroxy)phenyl-3-nitropiperidine (FTase: IC50 = 5.4 nM) resulted in metabolically stable compounds with more potent FTase inhibition than the parent compound. The reported SAR analysis showed that the introduction of substituents ortho to the hydroxy group of the C-2 benzene ring (nitro or iodo groups) reduced activity, while methoxy derivatives showed some activity against FTase (IC50 = 180 nM). Interestingly, orthoamino derivatives retained FTase inhibitory potency. The binding mode of the piperidine derivatives in the Ras protein-binding site of FTase indicated the presence of three hydrogen bonds: 1) between the O atom of the 3-nitro group and the OH group of Ser98, 2) between the N atom of the C-1 pyridine and Zn2+ ion of the protein, and 3) between the OH on the C-2 phenyl group and the O atom of Asp359. The binding models suggested that the ortho position of the phenolic hydroxyl group may be near to the edge of the binding pocket and directly outside of the protein, and the hydroxyl group might be important to form the hydrogen bond. Also the presence of bromo and ethyl groups at the C4 phenyl ring did not greatly affect glucouronidation.

The QSAR studies performed in our laboratory suggested that the FTase inhibitory activity mediated by the vdW surface area features properties such as partial charge (PEOE_VSA and Q_VSA) and v_surf features (hydrophobic integy moment) of the molecules. The fractional negative charge on the vdW surface of the molecules can interact with the Zn2+ ion in the active site. The hydrophobic volsurf property (integy moment) reveals that a clear separation between the hydrophobic and the hydrophilic region in the molecules is important with electrostatic groups (fractional negative charge), for better activity [21, 141] (Fig. 8G). 8.

This benzofuran derivative is a structural analogue to tipifarnib, which was reported by Asoh et al., [142]. The SAR studies suggested that the cyano group plays a major role for the inhibitory activity. Introduction of a cyano or a nitro group on the A-ring resulted in significant increase of the FTase inhibitory activities (IC50 = 6.4 and 30 nM, respectively). Replacement of a chlorine atom with another halogen, t-butylester, carboxylic acid, or methoxy resulted in reduction of FTase inhibitory activity (IC50 from 250 to 1000 nM). The compounds having a meta cyano group showed potent FTase inhibitory activity (IC50 = 2.8 nM) and antiproliferative activity (23 nM). The hydrogen bonding between the cyano group on the A-ring and Arg202 improves the enzyme inhibitory activity (PDB 2ZIS and 2ZIR). X-ray crystal structure of FTase with its most active compound, revealed a bridging water molecule forming hydrogen bonding between the oxygen atom of the carbonyl in substituent R2 on the benzofuran and the amide back bone of the Phe360 (PDB 2ZIS and 2ZIR). Substituent of small functional group at the B-ring (R3 position) increased antiproliferative activity against human cancer cell lines. Replacement of a nitro group with the carbonyl group increases the activity, forming hydrogen bonds between the oxygen atom of a carbonyl group and water in the active site. Not only carbonyl groups in R2 position but also the introduction of some HBA group at the R2 position is essential for improved inhibitory activities both in enzyme and cellular assays [142].

Structural Analysis of FTase Inhibitors

8F The QSAR studies conducted by Moorthy et al., [143] revealed that the models derived against the FTase inhibitory activity demonstrated that the P-VSA descriptors (vdW surface area descriptors) such as vsa_pol, vsa_acc and SMR_VSA3 are the major contributors for the activity along with other descriptors such as the partition coefficient, the partial charge, the atom and bond count, the adjacency and distance descriptors. The study against the antiproliferative activity showed that the partition coefficient (BCUT_SlogP and logP(o/w)) and PEOE_VSA4 of the molecules are detrimental for the activity, while the hydrogen bond acceptor and donor groups on the vdW surface of the molecules are favourable for the antiproliferative activity. These analyses highlighted that the positively charged groups on the active site of the enzyme or receptor (possibly the Arg202 amino acid residue and the Zn2+ ion), and the existence of hydrogen bond donor and acceptor groups on the vdW surface area of the molecules, and negatively charged groups in their structures are important for favourable activity [143] (Fig. 8H). 9.

Computational methodologies including molecular dynamics, density functional theory, virtual screening, absorption, distribution, metabolism, excretion and toxicity (ADMET) predictions and molecular interaction field studies [144-147] were carried out on potent FTIs, such as SCH226734, R115777 (tipifarnib), SCH66336 (lonafarnib), BMS 214662, L-778123 and U49. The study revealed that tipifarnib is more consistent with a better pharmacotherapeutic profile, in comparison with lonafarnib (another potent FTI). Tipifarnib has also more affinity with FTase than lonafarnib, which was confirmed through their correlation with logP as well as shape properties and vdW interactions. Molecular interaction fields (MIFs) obtained with the DRY (hydrophobic) and aromatic Csp2 probes, described the important role of the imidazole, quinolinone and chloro-benzene rings of tipifarnib for FTase inhibition. The chlorobenzene and imidazole rings of lonafarnib or L-778123 also bind to the same binding sites as the tipifarnib. MIFs pointed out that replacement of the oxygen atom present in the quinolinone moiety of tipifarnib by a hydrophobic atom/group improved the interaction. The substitution of cyanide in place of chlorine in the chlorobenzene ring of lonafarnib, converted the compound into a strong net of vdW contacts (including dipole-induced dipole interactions) with the W102 and W303 residues as well as the FTase substrate [144-147] (Fig. 8I).

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8G 10. A 2D spatial autocorrelation vector analysis was performed on 49 piperidine substituted trihalobenzocycloheptapyridine analogues (thBCHPs) as FTIs, which was reported by Fernandez et al., [148-151]. The multiple linear regression analysis (MLRA) model possessed three descriptors, and was able to explain about 68% data variance, while the non-linear model provided 92% data variance. The correlations derived from the autocorrelation coefficients weighted by vdW volumes and atomic polarizabilities on the inhibitor molecules. The model, derived with ANN, possessed good predictive power. The biggest difference among the interpretation of two models (linear and non-linear) is evidenced in the shortest-lag term weighted by volumes that appears in the linear model but not in the non-linear one. The lagone descriptors do not differentiate between linear and branched structural templates and are sensible to branched topological forms. The reported literature on the piperidine substitution in thBCHPS, explained that the piperidine is directed in the hydrophobic shallow channel away from the core of FTase interacting with aromatic residues (Trp102, Trp106 and Tyr361). Substitutions in the piperidine and the number of carbon atoms in the linker between the substituent and the piperidine ring play an important role to modulate the inhibitory activity. The vdW volume and polarizability as physicochemical weighting components influence the inhibitory activity. Additionally, the physicochemical weighting components obtained from the substituent influence the activity [148-151] (Fig. 8J). 11. Sung et al., [152, 153] has reported 3D-QSAR studies on 59 cinnamaldehyde analogues as FTase inhibitors using CoMFA with the partial least square (PLS) regionfocusing method. The CoMFA models (with region focusing method) developed with a grid spacing of 2 Å showed good statistical results (r2nov =0.950), and demonstrated that the steric and electrostatic field contributed superiorly (66:34) for the interaction. It revealed that a smaller ortho substituent on the benzyloxy group at the R1 position favoured the activity, and substitutions (bulky) in the meta and para positions are unfavourable. The steric and electrostatic properties of cinnamaldehyde analogues suggested that small bulky substitutions (methyl and methoxy), especially on the meta position of the aromatic ring (at R1 site), are favourable for the activity [152, 153] (Fig. 8K).

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8I

8J

8K

12. CoMFA and CoMSIA analysis of a series of 2,3-bisbenzylidenesuccinaldehyde derivatives (29 compounds) provided statistically optimized CoMFA (r2cv= 0.693 and r2ncv= 0.974) and CoMSIA models (r2cv = 0.484 and r2ncv= 0.928). The graphical interpretation of the results suggested that the inhibitory activity exhibited a strong correlation with steric factors of the substrate molecules. The steric favoured groups are in the meta and para positions of the terminal phenyl substitutions. These substituent positions also play a significant role (ortho and para substituents) increasing the activity. A formyl substitution indicates the electrostatic regions where the positive charge substituents increase the inhibitory activity [154] (Fig. 8L).

8L 13. Polloy et al., [149] have reported a Bayesian regularized neural network QSAR analysis on a large, diverse data

set of FTIs. In this analysis, researchers used novel molecular descriptors based on binned atomic properties and invariants of molecular matrices. Among the most relevant descriptors, the numbers of sp2-hybridized oxygen, sp2-hybridized sulphur, sulphate sulphur atoms, the numbers of five- and six-membered rings, 6 out of the 10 Burden indices (topological descriptor which describes the molecular graph), the occupancy of medium and high nitrogen charge bins, low and high oxygen charge bins and the occupancy of low-charge sulphur atoms (atomistic descriptors are of a type that describe either potential molecular hydrogen bond interactions (sp2-hybridized oxygen) or charge interactions (e.g., sulphate atoms or charges). The electrostatic potential of the sulphate sulphur atom counts and high charge bin phosphorus count, mimick the diphosphate group of the farnesyldiphosphate cofactor for favourable activity, while the sp2-hybridized sulphur count and low-charge sulphur count, hinder the activity. The hydrogen and carbon binned charge descriptors are important for the hydrophobic part of the molecules, which elicit the hydrophobic effect in the binding site [149, 155, 156]. 14. A 3D pharmacophore model (hypothesis) was reported on the prototype 1-(4-pyridylacetyl)-4-(8-chloro-5,6dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11ylidene)piperidine derivatives [157-161]. The pharmacophore model constitutes of four hydrophobic regions (the 3-methyl group on the pyridyl portion of the tricyclic system, the 5,6-ethano bridge of the tricyclic system, the aromatic ring of the 8-chlorophenyl portion of

Structural Analysis of FTase Inhibitors

the tricyclic system and the 4-pyridyl ring of the picolinamide attached to the pendent piperylidenyl ring) and one hydrogen bond acceptor site (the carbonyl group of the -picolinamide attached to the pendent piperylidenyl ring). The study concluded that the presence of a lipophilic alkyloxy or lipophilic action of the dihydrobenzothiophene and imidazole rings is necessary for the activity. Modification of an imidazole ring causes loss of activity even replaced with other amine heterocycles, and introduction of halogen to the aromatic and heteroaromatic rings (thiophene) increases the activity. The substitution of Cl in the benzothiophene at the 8th position also increased the activity. The fusion of a cyclohexyl ring to benzothiophene has some effect on the activity. Oxidation of the sulphur atom in dihydrobenzothiophene has less potent activity than their counter part. The geometric isomerism of the compounds reported that the S isomer has a preferred effect over the R isomer. Only three of the four possible hydrophobic regions of the FPT hypothesis map to the molecule, i.e. the piperazine ring of the side chain, and the aromatic ring and sulphur atom of the dihydrobenzothiophene ring system. The hydrogen bond acceptor in the generated FPT hypothesis is identified as the sulphur atom in the thiadiazine ring system. These suggested that the unoxidized sulphur atom is important for the inhibitory activity [157-161] (Fig. 8M). 15. In order to identify “activity trends” (an approach normally called a “directional” approach) and QSAR analysis for a congeneric series of FTIs, the benzo[f]perhydroisoindole (BPHI) series was performed by Giraud et al., [162] using PLS and principal component analysis (PCA) methods. The response surface modeling (RSM) was used to know the “activity trends” and the information obtained from the representative compound, which showed that an acid or ester group at position 3a of the molecule and an amide or related chemical group at this position (3a) have favourable activity. Also the acid group in the 3a position and small ortho substitution (methoxy group) at the phenyl ring of the side chain are favourable. The absence of a carboxylic acid and the steric hindrance of the ortho substitution are the main unfavourable structural characteristics [162] (Fig. 8N). 16. A 3D-QSAR CoMFA/CoMSIA investigation of 95 diaminobenzophenones yeast FTase showed that steric, electrostatic, and hydrophobic properties play key roles in the bioactivity of the series [163]. 17. A QSAR work performed on the imidazole containing tetrahydrobenzodiazepine compounds showed that KierA3 shape indices and polarizability on the molecules correlated better as far as the FTase inhibitory activity is concerned [164]. Another research work reported by the researchers illustrated that the volume, shape, flexibility and polarity of the FTIs are important for the inhibitory activities [165]. 18. In this analysis, authors have performed a QSAR study on the FTase inhibitory activity, human ether a-go-go related gene (hERG) blocking, and toxicity of the compounds [166, 167]. The selected models showed that the

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polar and polarisable properties on the vdW surface area of the molecules are important for the FTase inhibitory and hERG blocking activities, while being detrimental for the toxicity of the molecules. The topological properties, molecular flexibility and connectivity of the molecules are positively correlated to all these activities (FTase inhibition, hERG blocking and toxicity). The FTase models described that the fractional negative charge on the vdW surface of the molecule (PEOE_VSA_FNEG) is favourable for interaction with the Zn2+ ion and other positively charged amino acid residues in the active site. The distance between the hydrophobic and hydrophilic region in the molecule and the target should be high. The molecules should have more single bonds when they are in acyclic structure and this suggests that the compounds that exhibit flexible acyclic structure can have significant FTase inhibitory activity [166, 167] (Fig. 8O). 19. A QSAR report was published on Plasmodium falciparum and Rat protein farnesyltransferase (PFT) inhibitory activities of 6-cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-3-substituted-1,2,3,4-tetrahydroquinoline (THQ) analogues by Gupta et al., [17, 168]. The compounds in this series are structural analogues to BMS214662 (benzodiazepine analogue has reported activity). The PEOE_VSA+2 descriptor equally contributed to the PfePFT and RePFT inhibitory activities, analysed through the PLS method. The other descriptors such as partially charged surface areas in the range -0.20 to 0.15 (PEOE_VSA_3) and -0.30 to -0.25 (PEOE_VSA_5), a_hyd, logP(o/w), electronic energy (PM3_Eele) and Slog P_VSA4 of the molecules possessed significant effect on the PfePFT/RePFT inhibitory activities of the compounds. In these compounds, a_hyd and logP(o/w) influence the RePFT inhibitory activity more dominantly when compared to that of PfePFT. RePFT results showed that the presence of oxygen on sulphonamide and –N= of imidazole rings (C & D) is important to have significant PEOE_VSA_4 values and highly polarized carbon of D & E regions contribute to PEOE_VSA+6. Some other descriptors such as PEOE_VSA-3, E_str and a_hyd are common for both the FTase inhibitory activities alongwith the polarizable vdW surface area properties. The contributed descriptors in the models suggested the following: decreased PEOE_VSA-3 of pyridyl nitrogen in E ring and decreased PEOE_VSA-5 of N and /or O2 in E and D rings region are favourable for the PfPFT inhibitory activity. However, the presence of –CH= group at the D ring improve the PEOE_VSA+2 values causing favourable activity. Another important fragment in this compound is nitrile groups (cyano) and imidazole rings; as mentioned earlier these groups have possible favourable effect on the descriptor values. The substitution of nitrile group in the A ring decreased the PEOE_VSA-3 values and the substitution of less hydrophobic atoms (polar atom/groups) on the C ring (imidazole ring) are favourable for the inhibitory activity. These results clearly differentiated the THQ analogues’ requirements for PfePFT and RePFT inhibitory activities and set direction for achieving the desired selectivity [17, 49, 169] (Fig. 8P).

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8N 20. Xie et al., [2] reported a CoMFA and CoMSIA analyses on a data set of 2,5-diaminobenzophenone scaffold containing compounds which exhibited substituent variation in the aromatic rings (phenyl ring). The data set compounds displayed a wide range of activity against the multi-drug resistant Plasmodium falciparum strain Dd2 in submicromolar level. This research group has reported many CoMFA and other studies on FTIs [2, 132, 163]. The researchers have discussed the effect of the substituents (R1 and R2) in the inhibitory activity.

R1 substitutions: The CoMSIA map revealed that the bulky substituents on the terminal phenyl ring improve the inhibitory activity, while the CoMFA map pointed out the bulky groups that only in the para and meta positions are beneficial; the ortho position does not tolerate bulky substituents. Furthermore, there are limitations in that the para position needs bulky, but not too bulky or long chain, groups. Nitro substitutions at ortho and meta positions are unfavourable (nitro is bulkier than H) but the para position of the phenyl ring with closer electronwithdrawing and far

Structural Analysis of FTase Inhibitors

away donating groups are favourable for the activity. The electrostatic potential mainly due to hydrogen bond acceptor groups at the para position, while nitro groups at para position worsened the activity. These results show that a balance between the electrostatic potential and bulky groups in the para position is important.

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The author designed these compounds by substructures of the three most active compounds of series 1 and the two most active compounds of series 2, combining them. Compounds C and D exhibited relatively high, predicted activities (pIC50 = 8). The potential binding sites of FTase are calculated in the cavity size of 969 Å3 (close to important amino acid residues) There is a residue, Tyr361, potentially capable of providing specific cation interaction, therefore stabilizing the complex between FTase and the four compounds. Nmethylimidazole ring in those compounds was close to the Zn2+ ion (electrostatic interactions) and interacted with Tyr300 in contrast to compounds C and D [17, 129, 177] (Fig. 8R). FTIs FROM NATURAL PRODUCTS

8O R2 substitutions: The substitutions at the R2 position (ortho) showed that the presence of C-C (aromatic-substituent) carbon atom reduces the activity in relation to the unsubstituted compound. It further confirmed that substitutions such as ortho CF3, o-methyl, etc have less activity. However, bulky substituents in the meta position improve the activity as per the CoMFA and CoMSIA results. Meta methyl substituent and para amino in the R2 position of the ring increases the activity at the para position. It is interesting that some compounds having C-C bonds possessed better activity due to other properties on the molecules. Electronwithdrawing groups at para position of the phenyl ring increases, while electrondonating (methoxy) groups decrease the activity, even with favourable steric field. The para position needs small hydrophobic groups while large hydrophobic groups and branched chains decrease the activity, and the CF3 groups in the para position containing compounds have better activity. The authors concluded that steric, electrostatic and hydrophobic properties of substituent groups especially in the para position play key roles in the bioactivity of the series of compounds, while hydrogen bonding interactions show no obvious impact [2, 43, 170-175] (Fig. 8Q). The MIA-QSAR report on 2,5 diamino benzophenone derivatives also reveals that the CoMFA method is significant to explain the FTase inhibitory activity of these derivatives [176]. 21. Multivariate image analysis was applied to quantitative structure-activity relationship (MIA-QSAR) analysis on tetrahydroquinoline (series 1 from compound 1 to 24) and benzonitrile analogs (series 2 from compound 25 to 66) by Deeb et al., [177]. This research group proposed four compounds from the analysis, which had undergone docking and ADME studies and the results showed that hydrogen bonds between the compounds (C and D) and the active-site amino acid residues Tyr 365 and Tyr 361, in addition to interactions involving the Zn2+ ion present in the active site close to imidazole ring, are of great importance.

Recent studies reported in the literature showed that many FTIs have been isolated from natural products, those possessed selective and dual action with the prenyltransferase enzymes. Structures of the FTIs obtained from natural sources are provided in (Fig. 9). Marine sponges of the genus Xestospongia (Desmospongia Class, Haplosclerida Order, Petrosiidae family) are used to isolate a number of halenaquinone-type polyketides using bioassay directed fractionation techniques. Two novel derivatives named xestosaprol C methylacetal (9A) and orhalquinone (9B) included in the isolated derivatives. The three active molecules including orhalquinone (IC50 = 0.41±0.03 M and IC50 = 9.22±0.44 M), 3-ketoadociaquinone A (9C) (IC50 = 4.19±0.62 M and IC50 = 1.08±0.07 M) and 3ketoadociaquinone B (9D) (IC50 = 9.27±0.91 M and IC50 = 3.89±0.16 M) are also active in the FTase assays (FTase and GGTase enzymes) [178-183]. Orhalquinone (9B) displayed a significant inhibitory activity against both human and yeast FTase enzymes (obviously correlated the activity with P. falciparum), with IC50 value of 0.40 M and is a moderate growth inhibitor of P. falciparum. Halenaquinone (9E) (IC50 = 0.93±0.18 M), halenaquinol sulphate (9F) (IC50= 21.51±2.16 M) and xestosaprol C methylacetal (9A) (IC50 = 4.34±0.36 M) possessed significant inhibitory activity against human FTase in M range [43, 178-185]. Manumycin (9G) (a natural FTI) possessed apoptic effect on interleukin-6 (IL-6) producing myeloma cells that are resistant to Ras, dexamethasone and doxorubicin-induced apoptosis. The apoptogenic effect of this drug (treatment of MCC-2, IM-9 and U-266 cell lines) was related to the appearance of the unfarnesylated form of Ras protein, indicating that manumycin specifically prevents Ras activation [76, 186-189]. A methanolic extract of the leaves of Xanthium strumarium L. (Asteraceae) exhibited two xanthanolide sesquiterpene lactones, 8-epi-xanthatin (9H) and 8-epi-xanthatin epoxide (9I) which demonstrated a significant inhibition (inhibit the farnesylation process of human lamin-B FTase) on the proliferation of cultured human tumor cells, i. e. A549 (non-small cell lung), SK-OV-3 (ovary), SK-MEL-2 (melanoma), XF498 (central nervous system) and HCT-15 (colon) in vitro at higher concentrations (IC50 = 64 and 58 mM, respectively) [190, 191].

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8Q

8R Fig. (8). Graphical representation of the results obtained from QSAR and other computational analyses by different researchers on FTIs.

Structural Analysis of FTase Inhibitors

The most active single compound from this extract, 8epixanthatin 1,5-epoxide (9I) showed IC50 values of 0.09, 2.95, 0.16 and 1.71 μg/mL (0.33, 11.3, 0.6 and 6.5 μM) against T. brucei rhodesiense, T. cruzi, L. donovani and P. falciparum, respectively, while its cytotoxicity against rat myoblast cells (as control) was determined at 5.8 μg/mL (22.1 μM). Another two modified xanthanolide sesquiterpene lactones, (xanthipungolide (9J) and 4,15-dinor1,11(13)-xanthadiene-3,5:12,8-diolide (diversifolide (9K)) are also isolated from the same plant leaves. The xanthipungolide possessed no inhibitory activity against the tested parasites, and the diversifolide showed significant activity against T. brucei rhodesiense and L. donovani. The SAR of the reported xanthanolides has revealed that the methylene--lactone ring is an essential moiety for biological activity, such as antiproliferative, gastric cytoprotective and antileishmanial effects [192-199]. Kwon et al., [200] have isolated three potent FTIs (2hydroxycinnamaldehyde (9L), rhombenone (9M) and arteminolide (9N)) from herbal medicines. 2-Hydroxycinnamaldehyde has been isolated from the stem bark of Cinnamomum cassia Blume (Lauracea), rhombenone from the leaves of Hedera rhombea Bean (Araliaceae), while arteminolide has been isolated from the leaves of Artemisia sylvatica Maxim (Compositae). Members of the Artemisia genus are important medicinal plants found throughout the world (artemisinin as antimalarial agent, which was isolated from Artemisia annua L) [200, 201]. Rhombenone (9M) inhibited a recombinant rat FTase with an IC50 of 2.3 M. Additionally, its leaves extract has been used as a therapeutic agent for various diseases including haemorrhage, chronic catarrh, jaundice, lithiasis, and convulsion. Arteminolide inhibited recombinant rat FTase with an IC50 of 360 nM and appeared to be selective for FTase inhibitory activity. It did not inhibit rat squalene synthase (IC50 » 200 M) and recombinant rat GGTase-I (IC50 »200 M) [200, 201]. Theaflavin (9O) an antioxidant polyphenol was extracted from Camellia sinensis (tea), as a potential inhibitor of FTase enzyme. The molecular dynamics and docking studies on theaflavin and tipifarnib showed that both compounds have identical interacting residues to the protein which suggested theaflavin has selectivity towards FTase by interaction with Zn2+ ion. In addition, teaflavin also makes additional three hydrogen bonds to lysine 164(), tyrosine 93(), phenylalanine 360() than the tipifarnib [202-204]. An ethylacetate (EtOAc) extract of Penicillium ribeum (IBT 16537) by high-speed counter current chromatography (HSCCC) and through UV-guided fractionation enabled the isolation of Atlantinone A (9P). This active compound has structural similarity to the andrastins (9Q), (potent anticancer drug properties as FTIs) [205]. The andrastins A, B and C (9Q) are isolated from the broth supernatant of the penicillium sp FO-3929 and purified by silica gel, ODS chromatography and HPLC. These molecules (andrastins A, B and C) exhibited FTase inhibitory activity at IC50 = 24.9, 47.7 and 13.3 M respectively [206, 207]. While P. solitum, P. discolor, P. commune and P. caseifulvum (all members of the section Fasciculata) readily produce atlantinone A [206208].

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Pepticinnamin E (9R) is a major product of the pepticinnamins, which are isolated from the culture of Streptomyces sp. OH-4652. Pepticinnamin E shows rather potent inhibitory activity against FTase with an IC50 of 0.3 μM and is the first competitive inhibitor derived from natural product (a naturally occurring bisubstrate inhibitor of FTase) [209, 210]. A highly potent pentapeptide (9S) showed FTase inhibitory activity with IC50 = 17 nM/L, antagonizing Ras in Xenopus oocytes [63, 211, 212]. In addition to pepticinnamin E, several other natural products have been identified as FTIs, such as fusidienol (9T), preussomerins (9U), gliotoxin (9V), 10'desmethoxystreptonigrin (9W), and cylindrol A (9X), inhibiting FTase non-competitively [63, 211, 212]. Fusidienol (9T) was isolated from extracts of the fungus Fusidium griseum. It is a tricyclic oxygen containing heterocycle, which inhibits bovine brain FTase with an IC50 = 300 nM [24, 213]. Preussomerins are a class of fungal metabolites, which are extracted from the coprophilous fungus preussia isomer and the endophytic fungus Harmonema dematioides. Preussomerins exhibited strong FTase inhibitory activity (IC50 = 1.2 μM) and GGTase-1 activity (IC50 = 20 μM) [24, 214]. A sulphur-containing mycotoxin (Gliotoxin (9V)) produced by several species of fungi, some of which are pathogens of humans such as Aspergillus, and also by species of Trichoderma, and Penicillium. Gliotoxin have modest FTase inhibitory activity (IC50 = 1.1 μM) and its acetyl derivative possessed IC50 = 4.4 μM activity [24, 215, 216]. Cylindrol A (9X) is a bicyclic resorcinaldehyde cyclohexanone propionate derivative isolated from Cylidrocarpon lucidum [217]. This bicyclic derivative inhibited bovine FTase at IC50 = 2.2 μM and showed no inhibitory activity against GGTase-1 [24, 217]. 10'-desmethoxystreptonigrin analog of streptonigrin (9W), isolated from fermentation broth of Streptomyces albus showed inhibitory effect on farnesylation of Ras P21 protein (IC50 value of 0.021 M), which is 3 fold more active than streptonigrin (IC50 = 0.066 M). Furthermore, this molecule (9W) possessed marked cytotoxicity action on different cancer cell lines. The structural analysis revealed that this compound (10` desmethoxy streptonigrin) is the intermediate of the streptonigrin biosynthesis [24, 218, 219]. Chaetomellic acids A and B (9Y and 9Z) are alkyl cis dicarboxylic acids isolated from Chaetomella acutiseta, with competitive action to that of FPP (Ki = 3.5 nM) and noncompetitive with respect to FTase. These inhibitors appear to be the first example of non-phosphorous containing FPP mimetic and have selective activity. Chaetomellic acid A (9Y) was found to be 3 times more active than chaetomellic acid B (9Z) (Ki = 55 nM and Ki = 185 nM respectively), but has poor activity against GGTase-I (Ki > 50 μM) and squalene synthetase (Ki ~ 150 μM) [24, 220, 221]. The disodium salt of 2-(9-(butylthio)nonyl)-3-methylmaleic acid, is an analogue of chaetomellic acid A, with more competent FTase inhibitory activity than the latter [222]. A macrocyclic bis-lactone of actinoplanic acid (Actinoplanic acid A (9AA)) and an acyclic polycarboxlic acid (Actinoplanic acid B (9AB)) contain five free carboxylic acids. These compounds do not have effect on either human squalene synthase or bovine brain GGTase (Ki = >1 μM) [24, 220, 223]. Those are found to be competitive with

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Fig. (9). Structure of FTI isolated from natural products.

respect to FPP (Ki = 98 and 8 nM, respectively, for A and B) and uncompetitive with respect to Ras-CVIM [24, 220, 223, 224]. Another natural product containing multiple carboxylate groups such as Zaragozic acid (9AC) analogues, are competitive with binding to PFTase (IC50 = 50 nM) [24, 225]. Kaneko and co-workers at Pfizer described the isolation of CP-225917 (9AD) and CP-263114 (9AE) from unidentified fungus, which possessed FTase inhibitory activity at IC50 = 6 and 20 μM respectively) [24, 225]. NOVEL DEVELOPMENT AND CLINICAL FTIs Currently, significant research is in progress for the development of novel FTIs against cancer and other diseases. The outcome of those studies has yielded many potential FTIs, which are currently in clinical trials (Fig. 10). In the clinical development, well known FTIs such as R115777 (Tipifarnib) (10A) [226], SCH-66336 (Sarasar, lonafarnib) (10B), L-778123 (clinical study has been terminated due to toxicity) [227, 228] (10C) and BMS-214662 (10D) [229] are in different clinical phase studies for the treatment of various cancers. Tipifarnib (10A) and BMS-214662 (10D) have been developed by the Johnson Research Foundation and BristolMyers Squibb, respectively [230]. Tipifarnib is a non-peptide quinolone analogue, and it is the first FTI submitted to FDA for approval for the treatment of acute myeloid leukemia (AML) in patients aged over 65, for the New Drug Application. Unfortunately, the FDA has not approved the drug in 2005 [231-233]. Compounds tipifarnib and lonafarnib, are reported to be highly selective inhibitors of FTase vs GGTase-I [85]. BMS-214662 is a non-peptide tetrahydro-

benzodiazepine compound, but it is selective toward FTase, showing no activity against GGTase-I [146, 234]. SCH 226734 (10E) and lonafarnib (10B) are members of a known class of tricyclic non-cytotoxic compounds with anticancer activity. Among these molecules, tipifarnib is in advanced clinical development since some phase III studies have already been completed [63, 235, 236]. A phase II study has completed recently for the evaluation of the efficacy of tipifarnib in patients with refractory or relapsed AML by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. [229]. A phase 2 study on the oral tipifarnib was conducted in 93 adult patients with relapsed or refractory lymphoma. These results indicate that tipifarnib has activity in lymphoma, particularly in heavily pretreated HL/T types, with little activity in follicular NHL [11]. Phase I/II studies on orally administered tipifarnib showed that it possesses antitumour activity against breast cancer and haematological malignancies, but the myelotoxicity and the neurotoxicity are dose-limiting toxicities associated with this study. Phase III trial comparing gemcitabine plus tipifarnib vs gemcitabine plus placebo in advanced pancreatic cancer has failed to demonstrate any survival benefit in the presence of tipifarnib [227, 228]. Clinical activity of tipifarnib in combination with bortezomib is undergoing to determine the safety, target inhibition and signals of patients with advanced acute leukemias. The preliminary results showed that tipifarnib and bortezomib combination in patients with advanced leukemias is well tolerated, which demonstrated that the relevant target

22 Current Medicinal Chemistry, 2013, Vol. 20, No. 1

Moorthy et al.

Structural Analysis of FTase Inhibitors

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23

Fig. (10). Novel FTI in clinical studies and development stages.

inhibition is associated with signals of clinical activity in patients with advanced and refractory acute leukemias [237, 238]. There are a number of phase I and II studies undergoing or completed for tipifarnib alone or in combination with other drugs for the treatment of various cancers. The details

of the clinical studies performed on tipifarnib are provided in (Table 2) [239]. Phase II study of lonafarnib has been conducted to improve the disease in patients with chronic or accelerated phase CML and is completed [240]. Phase IB study of

24 Current Medicinal Chemistry, 2013, Vol. 20, No. 1

Table 2.

Moorthy et al.

Clinical Studies Undergoing/Completed for tipifarnib and its Combination [239]

Clinical Study

Drugs

Target

Status

Study

Phase II

Tipifarnib

Multiple Myeloma

Completed; October 2012

Effectiveness of tipifarnib on the target

Phase II

Tipifarnib

Refractory or relapsed AML

Completed; January 2011

Effectiveness (response rate) and safety

Open label Phase II

Tipifarnib

Post-consolidation therapy for AML in patients age 60 years and older

Completed; April 2010

Prevent leukemia from coming back (relapsing).

Phase II

Tipifarnib

Relapsed, Refractory or Progressive Mantle Cell Lymphoma

Completed; March 2011

Efficacy and the safety profile and toxicity on target and not appropriate for autologous bone marrow transplantation

Phase II

Tipifarnib

Poor-risk AML and high-risk myelodysplasia (MDS)

Completed; January 2013

Effectiveness in treating AML or myelodysplastic syndrome in first complete remission

Phase II

Tipifarnib

Relapsed and refractory lymphoma

Completed; December 2012

Effectiveness in relapsed or refractory nonHodgkin's lymphoma.

Phase I

Tipifarnib

Myelodysplastic syndrome

Suspended in 2013 due to safety issue

Side effects and best dose response.

Phase I/II

Tipifarnib

Myeloproliferative disorders

Active, not recruiting; June 2011

Side effects and effectiveness in myeloproliferative disorders

Phase II

Tipifarnib

Advanced Non-Small Cell Lung Cancer (NSCLC)

Completed; August 2011

Effectiveness in patients with recurrent or metastatic NSCLC.

Phase II

Tipifarnib

Untreated AML in patients of age 70 or older

Completed; January 2013

Frequency and severity of toxicity

Phase III

Tipifarnib

AML

Active, not recruiting; January 2013

Preventing cancer recurrence in patients with AML

Phase II

Tipifarnib

Pediatric patients with neurofibromatosis type I and progressive plexiform neurofibromas

Completed; September 2012

Side effects are related to treatment.

Phase II

Tipifarnib

Elderly patients with previously untreated poor-risk acute myeloid leukemia”

Completed; March 2013

Response rate, survival rate, duration of response, toxicity, effect

Phase I/II

Tipifarnib plus Temozolomide

Glioblastoma multiforme

Completed; July 2012

Safety dose, slow the growth of brain tumors

Phase I

Tipifarnib with radiation therapy

Advanced pancreatic cancer

Active, not recruiting; February 2009

Side effects and best dose of tipifarnib when given together with radiation therapy.

Phase IB/II

Tipifarnib plus Docetaxel and Capecitabine

Stage IIIA or IIIB Breast Cancer

Completed; December 2012

Effectiveness of the combination

Phase II

Tipifarnib plus Capecitabine

Metastatic breast cancer

Completed; February 2013

Effectiveness of the combination

Phase II

Tipifarnib, Gemcitabine, and Cisplatin

Advanced NSCLC

Completed; January 2013

Effectiveness of combincation in treating patients who have stage III or stage IV NSCLC.

Phase II

Tipifarnib plus Trastuzumab

Advanced breast cancer

Withdrawn; June 2012

Effectiveness

Phase II

Letrozole With or Without Tipifarnib

Advanced breast cancer after antiestrogen therapy

Active, not recruiting; February 2011

Effectiveness.

Structural Analysis of FTase Inhibitors

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25

(Table 2) contd….

Clinical Study

Drugs

Target

Status

Study

Randomized Phase II

Radiation therapy with or without tipifarnib

Locally advanced pancreatic cancer

Completed; January 2013

Toxicity, feasibility survival rate study

Phase I/II

Idarubicin, Cytarabine, and Tipifarnib

Newly diagnosed myelodysplastic syndromes or acute myeloid leukemia

Completed; January 2013

Efficacy, dose escalation, toxicity

Phase I

Tipifarnib and Etoposide

Newly diagnosed myelodysplastic syndromes or acute myeloid leukemia

Completed; January 2013

Feasibility, tolerability, MTD, mechanism

Phase II

Letrozole plus Tipifarnib

Advanced breast cancer

Completed; January 2013

If the addition of tipifarnib to standard letrozole therapy leads to a better response to treatment for cancer in comparison to letrozole plus a placebo

Phase I

Tipifarnib plus Topotecan

Advanced solid tumors

Completed; November 2012

Effectiveness

lonafarnib with fenretinide (4-HPR) and gemcitabine for the advanced or recurrent head and neck cancer and the resectable primary liver neoplasms respectively, have been terminated/withdrawn due to their safety issues (maximum tolerated doses (MTD)). The phase I study of lonafarnib and temozolomide for toxicity, tolerated dose and the antitumor response on grade 3 and 4 malignant gliomas is completed [239]. A Phase II clinical trial using lonafarnib has began on 7th May 2007 at the Children’s Hospital, Boston, USA for the treatment of Progeria [241]. This phase II clinical trial has been carried out in twenty-five patients with HGPS, receiving the lonafarnib for a minimum period of 2 years. Lonafarnib is not commercially available in Canada or the United States and can only be administered in approved clinical trials [54]. The results derived from these studies in which lonafarnib therapy improved cardiovascular status of children with HGPS, by improving peripheral arterial stiffness, reflected by highly elevated pretherapy pulse wave velocity (PWV) (the accepted standard measure of vascular stiffness) and echodense common carotid arteries (failure of this organ system is the ultimate cause of mortality). This therapy also improved the bone structure and audiological status in the patients [54, 231-233]. An open label phase II study has undergone with the combination of zoledronic acid, pravastatin and lonafarnib for the treatment of HGPS and progeroid laminopathies. A recent study suggested that FTase interacted with microtubule end binding protein 1 (EB1), which is critical for the localization of EB1 to microtubule tips. This interaction facilitates the translocation of farnesylated substrates to cell membrane, adding to the mode of action of FTase. Inhibition of the FTase by the lonafarnib could block the action of EB1 that leads to the inhibition of angiogenesis [242]. BMS-214662 is the third FTI in clinical development [227, 228]. BMS-214662 significantly and selectively induced apoptosis in chronic myeloid leukemia (CML) stem cells compared with normal cells. Phase I clinical trial of the

BMS-214662 has shown promising suggestions of single agent activity in patients with advanced solid tumors [63, 243, 244]. Phase I study on the combination of BMS-214662 plus trastuzumab against solid tumors has been completed. Another phase I study of the BMS-214662 alone has been completed for the effectiveness investigation against acute leukemias, myelodysplastic syndromes (RAEB and RAEBT) and CML in blast phase. The proteomic analysis of BMS214662 explained that the drug induces apoptosis in leukemia stem cells (LSCs) of CML patients. The study proposed that BMS-214662 altered proliferation of CML CD34+ cells via an Ebp1-dependent in CML patients [245]. The clinical study of L-778,123 using peripheral blood mononuclear cells (PBMCs) was carried out to measure the inhibition of prenylation of HDJ2 and Rap1A, proteins. The derived results showed that the pharmacological profile of L778,123 in humans as a dual inhibitor of FTase and GGTaseI, but indicated that the intended target of the drug, Ki-Ras, was not inhibited [246]. The single use of this drug L778,123 has been stopped in its clinical development due to its severe and unexpected toxicity, i.e. grade-4 thrombocytopenia and significant Q-T prolongation [227, 228]. In combination with paclitaxel, a phase I trial is undergoing to study the effectiveness in treating patients who have recurrent or refractory solid tumors or lymphomas [247]. The antitumor effect of another LB42708 (10F) can be associated with direct inhibition of vascular endothelial growth factor (VEGF) induced tumor angiogenesis by blocking Ras-dependent MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt/endothelial nitric-oxide synthase pathways in tumor-associated endothelial cells without altering FAK/Src activation (with IC50 values of 0.8 nM in vitro and 8 nM in cultured cells against p21-ras farnesylation). The inhibitory effect of LB42708 is significantly higher than that of lonafarnib. LB42708 suppressed tumor growth and angiogenesis in Ras-mutated HCT116 cells and its wild-type Caco-2 cells, indicate that it can be used for the treatment of both Ras mu-

26 Current Medicinal Chemistry, 2013, Vol. 20, No. 1

tated and wild type tumors [248-250]. Preclinical study of LB42908 (10G), a novel farnesyl transferase inhibitor, has been investigated. The species-specific in vitro metabolism studied in liver fractions of rat, dog, monkey and human showed that LB42908 is a potent CYP3A4 inhibitor in human liver microsomes and induced the activities of several CYP isozymes, implying that it has a potential for drug–drug interactions [251]. Investigation on macrocycle compounds provided informations that those compounds improve the pharmacokinetics and reduce the potential cardiac side effects of FTIs [101]. On account of this investigation, a piperazinone FTI (10C) (IC50 = 2 nM) (L-778123) was observed in a folded conformation (dynamic NMR studies), suggesting the opportunity to form cyclized analogue [252] such as connecting two ends of the linear 3-aminopyrrolidinone FTI (comp-1 (10H)) led to macrocycles such as compound (comp-2 (10I)), which displayed excellent oral bioavailability (F = 68%), a much longer half-life and reduced affinity for the hERG potassium channel [99, 101]. A315493 (10J) has strong inhibitory activity against FTase (IC50 = 0.4 nM) with potent cellular activity (EC50 = 8 nM) and exhibits good pharmacokinetic properties in dog and monkey. A comparison statement revealed that both A315493 and tipifarnib share quite a few common binding characteristics. Both of them have an N-methylimidazole ring that presumably interacts with the Zn2+ ion in the catalytic site of FTase [79, 85]. The interaction of a novel GDP exchange inhibitor Nglucosylated sulphonamide SCH-54292 (10K) with the RasGDP protein was studied by NMR spectroscopy. This drug plays a similar role as the antibody in freezing the conformation of the switch II region and thereby inhibiting the nucleotide exchange process. Recently the structural analogue of these molecules and SCH-54292 are used to evaluate binding to H-Ras by NMR experiments [253, 254]. AZD3409 (Fig. 4) is an orally active double prodrug and phase I pharmacokinetic (MTD, toxicity) and pharmacodynamic studies are undergoing on patients with solid malignancies with 500 mg once a day. The ester prodrug has broken down by esterases to form circulating metabolite

Fig. (11). Graphical representation of SAR of CAAX peptidomimetics.

Moorthy et al.

AZD3409 ester and finally converted into AZD3409 acid in the cell by intracellular esterases [69, 255, 256]. L-744832 (10L) is a selective thiol containing peptidomimetic FTI with antitumor properties. It is used for the treatment of 5 different human pancreatic cancer cell lines, resulting in inhibition of anchorage dependent growth. It rapidly blocks p70S6K activation and DNA synthesis and promotes apoptosis in transgenic mice. Additionally, it induces p21 expression and cell cycle arrest in the G1 phase. L744832 at a concentration of 1 μM additively enhanced the cytotoxic effect of ionizing radiation, apparently by overriding the G2/M check point activation [257]. The phosphinic acid derivative BMS-186511 (10M) is a bisubstrate FTI (IC50 = 21 μM). The methyl ester prodrug of BMS-186511 at μM showed 75-80% decrease in colony formation in soft agar. The inhibition of FTase activity in cells and the Ras transformed cell growth is further manifested in distinct morphological changes in cells. Effects of BMS-186511 are limited to Ras transformed cells that utilize the farnesylated Ras, but are not seen in transformed cells that use geranylgeranyl Ras or myristoyl Ras [24, 258]. The FTase enzyme has been a target for anticancer and antiparasite drug discovery. Initially, the CAAX template was used to develop peptidomimetics, subsequently non-peptides, non-thiol, heterocyclic and macrocycle derivatives etc were used as FTIs. SAR of the CAAX peptidomimetics (Fig. 11) showed that thiol moiety of the cystine residue interact with the Zn2+ ion. At a later stage, the thiol was replaced with imidazole and/or other heterocyclic/aryl rings and those compounds provided selective and potent FTase inhibitory activity. Recently, phenothiazine and ferrocene substituted FTI were discovered, which have significant inhibitory activity [259]. The presence of high and medium hydrophobic parts in the molecules is important for the inhibitory activity. Phenothiazine containing FTIs are able to coordinate with the Zn2+ ion of the protein via chelating groups and the bulky phenothiazine unit interacts with the A2 binding site [97, 98, 259]. The aryl/heteroaryl and substituted aryl/heteroaryl rings in the molecules are used to fulfil this hydrophobic requirement. QSAR results of the reported literatures are summarized as the graphical representation in (Fig. 12).

Structural Analysis of FTase Inhibitors

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27

Fig. (12). Graphical representation of the results of the QSAR and other computational analyses on FTIs (summary of the studies).

These results showed that the presence of heterocycle or some polar group in place of thiol is necessary for the interaction with the Zn2+ ion. As discussed earlier, the imidazole or fused imidazole nucleus is a better choice for this position. Bulky hydrophobic substitutions in the molecules have hydrophobic interaction with the aromatic aminoacid moieties in the hydrophobic pocket. The naphthyl, quinolinyl, phenyl groups, phenothiazine, etc in this position provides better hydrophobicity for the molecules. The presence of a methyl or methoxy group (ortho/para positions) with the cyano group (meta/para positions) in the phenyl ring makes the region of molecules with medium hydrophobicity or balanced (hydrophobicity and hydrophilicity), which establishes an interaction with the arginine residue in the active region. A hydrophilic region with polar groups is necessary for the polar or hydrogen bonding interactions with the amino acids or water molecules present in the active site. The aromatic groups in this position may have interaction with the delocalized charged guanidinium group in the arginine residue (Figs. 13 and 14). Mostly, the electronegative substitution at the meta and para positions of the aryl ring possessed significant effect. The hydrophilic group containing position may undergo an interaction with some polar amino acids and water molecules in the active site. There have been many FTIs isolated from the natural products, which possessed activity against FTase and GGTase-1 enzymes. Among them, pepticinnamin E (9R), fusidienol (9T), gliotoxin (9V), cylindrol A (9X), etc possessed potential FTase inhibitory activities. It is interesting that most of the FTase inhibitors isolated from the natural products are rigid in structure, but have significant activity. These compounds have rigid ring structure, some polar substituents in different positions and either an aliphatic or aromatic side chain to provide hydrophobicity of

the molecules as the synthetic molecules. Figs. 13 and 14 revealed that the active site of the enzyme has pocket like structure, in which each groups can interact with different amino acids in position. CONCLUSION This review concluded that the structural analysis of the synthetic compounds provide some information on the polar substituents, i.e. flexibility of bonds and either aliphatic or aromatic side chains (to provide hydrophobicity) are important for the FTase inhibitory activity. The natural product compounds with rigid structures also possess significant inhibitory activity on the FTase enzyme. The quantitative structural analysis reports with an elaborative study on the natural product compounds will provide information on the rigid molecules for the FTase inhibitory activity. The clinical studies on different FTIs showed that the tipifarnib has been used for the treatment of various types of cancers. Lonafarnib is also in the phase II clinical study for the treatment of Hutchinson-Gilford Progeria Syndrome in children. BMS-214662 induces apoptosis in CML patients. Some clinical studies of the FTIs alone or in combination for the treatment of cancer or other diseases failed due to its toxicity and safety issues. Hence, the development of pharmacokinetic compatible drug molecules is important for the treatment of cancer and other diseases. The fragment-based analysis is needed to select the substituents, which can provide significant activity and also have good pharmacokinetic properties. As mentioned earlier by researchers, macrocycles present in the molecules originate less cardiotoxicity and retain the FTase inhibitory activity. This review provides a guide for the development of novel FTIs for cancer and other diseases.

28 Current Medicinal Chemistry, 2013, Vol. 20, No. 1

Moorthy et al.

Fig. (13). Graphical representation of ligand interaction sites of rat protein farnesyltransferase complexed with a bezofuran inhibitor and FPP (PDB: 2ZIS).

Fig. (14). Ligand interaction sites of rat protein farnesyltransferase complexed with a bezofuran inhibitor and FPP (PDB: 2ZIS).

CONFLICT OF INTEREST

REFERENCES

The author(s) confirm that this article content has no conflicts of interest.

[1]

ACKNOWLEDGEMENTS N.S.H.N. Moorthy is grateful to the Fundação para a Ciência e Tecnologia (FCT), Portugal for a Postdoctoral Grant (SFRH/BPD/44469/2008).

[2]

[3]

Sousa, S.F.; Fernandes, P.A.; Ramos, M.J. Theoretical studies on farnesyltransferase: The distances paradox explained. Proteins: Struct. Function, Bioinformatics, 2007, 66, 205-218. Xie, A.; Sivaprakasam, P.; Doerksen, R.J. 3D-QSAR analysis of antimalarial farnesyltransferase inhibitors based on a 2,5diaminobenzophenone scaffold. Bioorg. Med. Chem., 2006, 14, 7311-7323. Yokoyama, K.; Trobridge, P.; Buckner, F.S.; Van Voorhis, W.C.; Stuart, K.D.; Gelb, M.H. Protein farnesyltransferase from Trypanosoma brucei. A heterodimer of 61- and 65-kda subunits as a new

Structural Analysis of FTase Inhibitors

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12] [13]

[14]

[15]

[16]

[17]

target for antiparasite therapeutics. J. Biol. Chem., 1998, 273, 26497-26505. Capell, B.C.; Erdos, M.R.; Madigan, J.P.; Fiordalisi, J.J.; Varga, R.; Conneely, K.N.; Gordon, L.B.; Der, C.J.; Cox, A.D.; Collins, F.C. Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson–Gilford progeria syndrome. Proc. Natl. Aacd. Sci. USA, 2005, 102, 12879-12884. Ohkanda, J.; Buckner, F.S.; Lockman, J.W.; Yokoyama, K.; Carrico, D.; Eastman, R.; Luca-Fradley, K.; Davies, W.; Croft, S.L.; Van Voorhis, W.C.; Gelb, M.H.; Sebti, S.M.; Hamilton, A.D. Design and synthesis of peptidomimetic protein farnesyltransferase inhibitors as anti-Trypanosoma brucei agents. J. Med. Chem., 2004, 47, 432-445. Buckner, F.S.; Eastman, R.T.; Nepomuceno-Silva, J.L.; Speelmon, E.C.; Myler, P.J.; Van Voorhis, W.C.; Yokoyama, K. Cloning, heterologous expression, and substrate specificities of protein farnesyltransferases from Trypanosoma cruzi and Leishmania major. Mol. Biochem. Parasitol., 2002, 122, 181-188. Esteva, M.I.; Kettler, K.; Maidana, C.; Fichera, L.; Ruiz, A.M.; Bontempi, E.J.; Andersson, B.; Dahse, H.M.; Haebel, P.; Ortmann, R.; Klebe, G.; Schlitzer, M. Benzophenone-based farnesyltransferase inhibitors with high activity against Trypanosoma cruzi. J. Med. Chem., 2005, 48, 7186-7191. Troutman, J.M.; Subramanian, T.; Andres, D.A.; Spielmann, H.P. Selective modification of CaaX peptides with ortho-substituted anilinogeranyl lipids by protein farnesyl transferase: Competitive substrates and potent inhibitors from a library of farnesyl diphosphate analogues. Biochemistry, 2007, 46, 11310-11321. Eastman, R.T.; White, J.; Hucke, O.; Bauer, K.; Yokoyama, K.; Nallan, L.; Chakrabarti, D.; Verlinde, C.L.; Gelb, M.H.; Rathod, P.K.; Van Voorhis, W.C. Resistance to a protein farnesyltransferase inhibitor in Plasmodium falciparum. J. Biol. Chem., 2005, 280, 13554-13559. Buckner, F.S.; Eastman, R.T.; Yokoyama, K.; Gelb, M.H.; Van Voorhis, W.C. Protein farnesyl transferase inhibitors for the treatment of malaria and African trypanosomiasis. Curr. Opin. Invest. Drugs, 2005, 6, 791-797. Witzig, T.E.; Tang, H.; Micallef, I.N.M.; Ansell, S.M.; Link, B.K.; Inwards, D.J.; Porrata, L.F.; Johnston, P.B.; Colgan, J.P.; Markovic, S.N.; Nowakowski, G.S.; Thompson, C.A.; Allmer, C.; Maurer, M.J.; Gupta, M.; Weiner, G.; Hohl, R.; Kurtin, P.J.; Ding, H.; Loegering, D.; Schneider, P.; Peterson, K.; Habermann, T.M.; Kaufmann, S.H. Multi-institutional phase 2 study of the farnesyltransferase inhibitor tipifarnib (R115777) in patients with relapsed and refractory lymphomas. Blood, 2011, 118, 4882-4889. Zhang, F.L.; Casey, P.J. Protein prenylation: Molecular mechanisms and functional consequences. Annu. Rev. Biochem., 1996, 65, 241-269. Fletcher, S.; Keaney, E.P.; Cummings, C.G.; Blaskovich, M.A.; Hast, M.A.; Glenn, M.P.; Chang, S.Y.; Bucher, C.J.; Floyd, R.J.; Katt, W.P.; Gelb, M.H.; Van Voorhis, W.C.; Beese, L.S.; Sebti, S.M.; Hamilton, A.D. Structure-based design and synthesis of potent, ethylenediamine-based, mammalian farnesyltransferase inhibitors as anticancer agents. J. Med. Chem., 2010, 53, 6867-6888. Wang, L.; Lin, N.H.; Li, Q.; Henry, R.F.; Zhang, H.; Cohen, J.; Gu, W.Z.; Marsh, K.C.; Bauch, J.L.; Rosenberg, S.H.; Sham, H.L. Synthesis of 1H-pyridin-2-one derivatives as potent and selective farnesyltransferase inhibitors. Bioorg. Med. Chem. Lett., 2004, 14, 4603-4606. Hast, M.A.; Fletcher, S.; Cummings, C.G.; Pusateri, E.E.; Blaskovich, M.A.; Rivas, K.; Gelb, M.H.; Van Voorhis, W.C.; Sebti, S.M.; Hamilton, A.D.; Beese1, L.S. Structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase. Chem. Biol., 2009, 16, 181-192. Ohkanda, J.; Lockman, J.W.; Yokoyama, K.; Gelb, M.H.; Croft, S.L.; Kendrick, H.; Harrell, M.I.; Feagin, J.E.; Blaskovich, M.A.; Sebti, S.M.; Hamilton, A.D. Peptidomimetic inhibitors of protein farnesyltransferase show potent antimalarial activity. Bioorg. Med. Chem. Lett., 2001, 11, 761-764. Gupta, M.K.; Prabhakar, Y.S. QSAR study on tetrahydroquinoline analogues as plasmodium protein farnesyltransferase inhibitors: A comparison of rationales of malarial and mammalian enzyme inhibitory activities for selectivity. Eur. J. Med. Chem., 2008, 43, 2751-2767.

Current Medicinal Chemistry, 2013, Vol. 20, No. 1 [18] [19] [20]

[21] [22] [23]

[24] [25] [26] [27] [28] [29]

[30]

[31] [32] [33]

[34] [35]

[36] [37] [38]

[39]

[40]

29

Sousa, S.F.; Fernandes, P.A.; Ramos, M.J. Farnesyltransferase inhibitors: A detailed chemical view on an elusive biological problem. Curr. Med. Chem., 2008, 15, 1478-1492. Sousa, S.F.; Fernandes, P.A.; Ramos, M.J., The search for the mechanism of the reaction catalyzed by farnesyltransferase. Chem. Eur. J., 2009, 15, 4243-4247. Margaritora, S.; Cesario, A.; Porziella, V.; Granone, P.; Catassi, A.; Russo, P. Farnesyltransferase inhibitors: overview of their action and role in solid malignancy therapy. Lett. Drug Des. Discov., 2005, 2, 26-35. Moorthy, N.S.H.N.; Sousa, S.F.; Ramos, M.J.; Fernandes, P.A. In silico based structural analysis of some piperidine analogs as farnesyltransferase inhibitors. Med. Chem., 2012, 8, 853-864. Long, S.B.; Casey, P.J.; Beese, L.S. Cocrystal structure of protein farnesytransferase complexed with a farnesyl diphosphate substrate. Biochemistry, 1998, 37, 9612-9618. Kyathanahalli, C.N.; Kowluru, A. A farnesylated G-protein suppresses Akt phosphorylation in INS 832/13 cells and normal rat islets: regulation by pertussis toxin and PGE (2). Biochem. Pharmacol., 2011, 81, 1237-1247. Ohkanda, J.; Knowles, D.B.; Blaskovich, M.A.; Sebti, S.; Hamilton, A.D. Inhibitors of protein farnesyltransferase as novel anticancer agents. Curr. Topics Med. Chem., 2002, 2, 303-323. Furfine, E.S.; Leban, J.J.; Landavazo, A.; Moomaw, J.F.; Casey, P.J. Protein farnesyltransferase: kinetics of farnesyl pyrophosphate binding and product release. Biochemistry, 1995, 34, 6857-6862. Hightower, K.E.; Huang, C.C.; Casey, P.J.; Fierke, C.A. H-Ras peptide and protein substrates bind protein farnesyltransferase as an ionized thiolate. Biochemistry, 1998, 37, 15555-15562. Sousa, S.F.; Fernandes, P.A.; Ramos, M.J. Farnesyltransferase: Theoretical studies on peptide substrate entrance thiol or thiolate coordination?. J. Mol. Struct. (Theochem), 2005, 729, 125-129. Saderholm, M.J.; Hightower, K.E.; Fierke, C.A. Role of metals in the reaction catalyzed by protein farnesyltransferase. Biochemistry, 2000, 39, 12398-12405. Long, S.B.; Hancock, P.J.; Kral, A.M.; Hellinga, H.W.; Beese, L.S. The crystal structure of human protein farnesyltransferase reveals the basis for inhibition by CaaX tetrapeptides and their mimetics. Proc. Natl. Acad. Sci. USA, 2001, 98, 12948-12953. Strickland, C.L.; Windsor, W.T.; Syto, R.; Wang, L.; Bond, R.; Wu, Z.; Schwartz, J.; Le, H.V.; Beese, L.S.; Weber, P.C. Crystal structure of farnesyl protein transferase complexed with a CaaX peptide and farnesyl diphosphate analogue. Biochemistry, 1998, 37, 16601-16611. Long, S.B.; Casey, P.J.; Beese, L.S. The basis for K-Ras4B binding specificity to protein farnesyltransferase revealed by 2 Å resolution ternary complex structures. Struct. Fold. Des., 2000, 8, 209-222. Long, S.B.; Casey, P.J.; Beese, L.S. Reaction path of protein farnesyltransferase at atomic resolution. Nature, 2002, 419, 645-650. Pickett, J.S.; Bowers, K.E.; Hartman, H.L.; Fu, H.W.; Embry, A.C.; Casey, P.J.; Fierke, C.A. Kinetic studies of protein farnesyltransferase mutants establish active substrate conformation. Biochemistry, 2003, 42, 9741-9748. Sousa, S.F.; Fernandes, P.A.; Ramos, M.J. Enzyme flexibility and the catalytic mechanism of farnesyltransferase: Targeting the relation. J. Phys. Chem. B, 2008, 112, 8681-8691. Olepu, S.; Suryadevara, P.M.; Rivas, K.; Yokoyama, K.; Verlinde, C.L.M.J.; Chakrabarti, D.; Van Voorhis, W.C.; Gelb, M.H. 2-Oxotetrahydro-1,8-naphthyridines as selective inhibitors of malarial protein farnesyltransferase and as anti-malarials. Bioorg. Med. Chem. Lett., 2008, 18, 494-497. Bos, J.L. Ras oncogenes in human cancer: A review. Cancer Res., 1989, 49, 4682-4689. Almoguera, C.; Shibata, D.; Forrester, K.; Martin, J.; Arnheim, N.; Perucho, M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell, 1988, 53, 549-554. Rodenhuis, S.; Slebos, R.J.; Boot, A.J.; Evers, S.G.; Mooi, W.J.; Wagenaar, S.S.; Van Bodegom, P.C.; Bos, J.L. Incidence and possible clinical significance of K-rai oncogene activation in adenocarcinoma of the human lung. Cancer Res., 1988, 48, 5738-5741. Bos, J.L.; Fearon, E.R.; Hamilton, S.R.; Verlaan-de Vries, M.; Van Boom, J.H.; Van der Eb, A.J.; Vogelstein, B. Prevalence of ras gene mutations in human colorectal cancer. Nature, 1987, 327, 293-297. Vogelstein, B.; Fearon, E.R.; Hamilton, A.D.; Kern, S.E.; Preisinger, A.C.; Leppert, M.; Nakamura, Y.; White, R.; Smits, A.M.;

30 Current Medicinal Chemistry, 2013, Vol. 20, No. 1

[41] [42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

Bos, J.L. Genetic alterations during colorectal-tumor development. New Engl. J. Med., 1988, 319, 525-532. www.plasmodb.org. Accessed on 22/04/2013. Chakrabarti, D.; Da Silva, T.; Barger, J.; Paquette, S.; Patel, H.; Patterson, S.; Allen, C.M. Protein farnesyltransferase and protein prenylation in Plasmodium falciparum. J. Biol. Chem., 2002, 277, 42066-42073. Wiesner, J.; Kettler, K.; Sakowski, J.; Ortmann, R.; Katzin, A.M.; Kimura, E.A.; Silber, K.; Klebe, G.; Jomaa, H.; Schlitzer, M. Farnesyltransferase inhibitors inhibit the growth of malaria parasites in vitro and in vivo. Angew. Chem., Int. Ed. Engl., 2004, 43, 251-254. Carrico, D.; Ohkanda, J.; Kendrick, H.; Yokoyama, K.; Blaskovich, M.A.; Bucher, C.J.; Buckner, F.S.; Van Voorhis, W.C.; Chakrabarti, D.; Croft, S.L.; Gelb, M.H.; Sebti, S.M.; Hamilton, A.D. In vitro and in vivo antimalarial activity of peptidomimetic protein farnesyltransferase inhibitors with improved membrane permeability. Bioorg. Med. Chem., 2004, 12, 6517-6526. Glenn, M.P.; Chang, S.Y.; Hucke, O.; Verlinde, C.L.; Rivas, K.; Horney, C.; Yokoyama, K.; Buckner, F.S.; Pendyala, P.R.; Chakrabarti, D.; Gelb, M.; Van Voorhis, W.C.; Sebti, S.M.; Hamilton, A.D. Structurally simple farnesyltransferase inhibitors arrest the growth of malaria parasites. Angew. Chem., Int. Ed. Engl., 2005, 44, 4903-4906. Ryckebusch, A.; Gilleron, P.; Millet, R.; Houssin, R.; Lemoine, A.; Pommery, N.; Grellier, P.; Sergheraert, C.; Henichart, J.P. Novel N-(4-piperidinyl)benzamide antimalarials with mammalian protein farnesyltransferase inhibitory activity. Chem. Pharm. Bull., 2005, 53, 1324-1326. Kettler, K.; Wiesner, J.; Silber, K.; Haebel, P.; Ortmann, R.; Sattler, I.; Dahse, H.M.; Jomaa, H.; Klebe, G.; Schlitzer, M. Non-thiol farnesyltransferase inhibitors: N-(4-aminoacylamino-3benzoylphenyl)-3-[5-(4-nitrophenyl)-2 furyl]acrylic acid amides and their antimalarial activity. Eur. J. Med. Chem., 2005, 40, 93101. Glenn, M.P.; Chang, S.Y.; Horney, C.; Rivas, K.; Yokoyama, K.; Pusateri, E.E.; Fletcher, S.; Cummings, C.G.; Buckner, F.S.; Pendyala, P.R.; Chakrabarti, D.; Sebti, S.M.; Gelb, M.; Van Voorhis, W.C.; Hamilton, A.D. Structurally simple, potent, Plasmodium selective farnesyltransferase inhibitors that arrest the growth of malaria parasites. J. Med. Chem., 2006, 49, 5710-5727. Nallan, L.; Bauer, K.D.; Bendale, P.; Rivas, K.; Yokoyama, K.; Horney, C.P.; Pendyala, P.R.; Floyd, D.; Lombardo, L.J.; Williams, D.K.; Hamilton, A.; Sebti, S.; Windsor, W.T.; Weber, P.C.; Buckner, F.S.; Chakrabarti, D.; Gelb, M.H.; Van Voorhis, W.C. Protein farnesyltransferase inhibitors exhibit potent antimalarial activity. J. Med. Chem., 2005, 48, 3704-3713. Gelb, M.H.; Brunsveld, L.; Hrycyna, C.A.; Michaelis, S.; Tamanoi, F.; Van Voorhis, W.C.; Waldmann, H. Therapeutic intervention based on protein prenylation and associated modifications. Nat. Chem. Biol., 2006, 2, 518-526. Eastman, R.T.; Buckner, F.S.; Yokoyama, K.; Gelb, M.H.; Van Voorhis, W.C. Thematic review series: lipid posttranslational modifications. Fighting parasitic disease by blocking protein farnesylation. J. Lipid Res., 2006, 47, 233-240. Kim, H.K.; Lee, J.Y.; Bae, E.J.; Oh, P.S.; Park, W.I.; Lee, D.S.; Kim, J.I.; Lee, H.J. Hutchinson–Gilford progeria syndrome with G608G LMNA mutation. J. Korean Med. Sci., 2011, 26, 16421645. Marji, J.; O’Donoghue, S.I.; McClintock, D.; Satagopam, V.P.; Schneider, R.; Ratner, D.; Worman, H.J.; Gordon, L.B.; Djabali, K. Defective Lamin A-Rb signaling in Hutchinson-Gilford progeria syndrome and reversal by farnesyltransferase inhibition. PLoS ONE, 2010, 5, e11132 (1-14). Parreno, J.; Cruz, A.V. Accelerated aging in patients with Hutchinson-Gilford progeria syndrome: Clinical signs, molecular causes, treatments, and insights into the aging process. UBC Med. J., 2011, 3, 8-12. Sebti, S.M.; Hamilton, A.D. Farnesyltransferase and geranylgeranyltransferase I inhibitors and cancer therapy: Lessons from mechanism and bench-to-bedside translational studies. Oncogene, 2000, 19, 6584-6593. Brown, M.S.; Goldstein, J.L.; Paris, K.J.; Burnier, J.P.; Marsters, J.C. Tetrapeptide inhibitors of protein farnesyltransferase: Aminoterminal substitution in phenylalanine-containing tetrapeptides restores farnesylation. Proc. Natl. Acad. Sci. USA, 1992, 89, 83138316.

Moorthy et al. [57]

[58]

[59]

[60] [61]

[62]

[63]

[64]

[65] [66] [67]

[68] [69]

[70] [71]

[72]

[73] [74]

[75]

Graham, S.L.; de Solms, S.J.; Giuliani, E.A.; Kohl, N.E.; Mosser, S.D.; Oliff, A.I.; Pompliano, D.L.; Rands, E.; Breslin, M.J.; Deana, A.A.; Garsky, V.M.; Scholz, T.H.; Gibbs, J.B.; Smith, R.L. Pseudopeptide inhibitors of ras farnesyl-protein transferase. J. Med. Chem., 1994, 37, 725-732. Leftheris, K.; Kline, T.; Natarajan, S.; DeVirgilio, M.K.; Cho, Y.H.; Pluscec, J.; Ricca, C.; Robinson, S.; Seizinger, B.R.; Manne, V.; Meyers, C.A. Peptide based p21 ras farnesyl transferase inhibitors: Systematic modification of the tetrapeptide CA1A2X motif. Bioorg. Med. Chem. Lett., 1994, 4, 887-892. Dinsmore, C.J., Bell, I.M., Inhibitors of farnesyltransferase and geranylgeranyltransferase-I for antitumor therapy: Substrate-based design, conformational constraint and biological activity, Curr. Topics Med. Chem. 2003, 3, 1075-1093. Goldstein, J.L.; Brown, M.S.; Stradley, S.J.; Reiss Y.; Gierasch, L.M. Nonfarnesylated tetrapeptide inhibitors of protein farnesyltransferase. J. Biol. Chem., 1991, 266, 15575-15578. Nigam, M.; Seong, C.M.; Qian, Y.; Hamilton, A.D.; Sebtim, S.M. Potent inhibition of human tumor p21ras farnesyltransferase by A1A2-lacking p2ras CA1A2X peptidomimetics. J. Biol. Chem., 1993, 268, 20695-20698. Reiss, Y.; Stradley, S.J.; Gierasch, L.M.; Brown, M.S.; Goldstein, J.L. Sequence requirement for peptide recognition by rat brain p2lras protein farnesyltransferase. Proc. Natl. Acad. Sci. USA, 1991, 88, 732-736. Agrawal, A.G.; Somani, R.R. Farnesyltransferase inhibitor in cancer treatment, Ozdemir, O., Current cancer treatment – Novel beyond conventional approaches, InTech Europe, Rijeka, Croatia. 2011, 150-172. Duque, G.; Vidal, C.; Rivas, D. Protein isoprenylation regulates osteogenic differentiation of mesenchymal stem cells: effect of alendronate, and farnesyl and geranylgeranyl transferase inhibitors. Br. J. Pharmacol., 2011, 162, 1109-1118. Symons, M. The Rac and Rho pathways as a source of drug targets for Ras-mediated malignancies. Curr. Opin. Biotechnol., 1995, 6, 668-774. Gibbs, J.B. Ras C-terminal processing enzymes—new drug targets?. Cell, 1991, 65, 1-4. Moores, S.L.; Schaber, M.D.; Mosser, S.D.; Rands, E.; O'Hara, M.B.; Garsky, V.M.; Marshall, M.S.; Pompliano, D.L.; Gibbs, J.B. Sequence dependence of protein isoprenylation. J. Biol. Chem., 1991, 266, 14603-14610. Wasko, B.M.; Dudakovic, A.; Hohl, R.J. Bisphosphonates induce autophagy by depleting geranylgeranyl diphosphate. J. Pharmacol. Exp. Ther., 2011, 337, 540-546. Appels, N.M.G.M.; Bolijn, M.J.; Chan, K.; Stephens, T.C.; HoctinBoes, G.; Middleton, M.; Beijnen, J.H.; de Bono, J.S.; Harris, A.L.; Schellens, J.H.M. Phase I pharmacokinetic and pharmacodynamic study of the prenyl transferase inhibitor AZD3409 in patients with advanced cancer. Br. J. Cancer, 2008, 98, 1951-1958. Casey, P.J.; Seabra, M.C. Protein prenyltransferases. J. Biol. Chem., 1996, 271, 5289-5292. Lerner, E.C.; Qiani, Y.; Blaskovich, M.A.; Fossum, R.D.; Vogt, A.; Sun, J.; Cox, A.D.; Der, C.J.; Hamilton, A.D.; Sebti, S.M. Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic ras signaling by inducing cytoplasmic accumulation of inactive RasRaf complexes. J. Biol. Chem., 1995, 270, 26802-26806. McGuire, T.; Qian, Y.; Hamilton, A.D.; Sebti, S.M. Platelet derived growth factor receptor tyrosine phosphorylation requires protein geranylgeranylation and not farnesylation. J. Biol. Chem., 1996, 271, 27402-27407. Vogt, A.; Qian, Y.; Hamilton, A.D.; Sebti, S.M. Protein geranylgeranylation, not farnesylation, is required for the G1 to S phase transition in mouse fibroblasts. Oncogene, 1996, 13, 1991-1999. Vogt, A.; Sun, J.; Qian, Y.; Hamilton, A.D.; Sebti, S.M. The geranylgeranyltransferase I inhibitor GGTI-298 arrests human tumor cells in G0/G1 and induces p21WAF/CIP/SDII in a-p53 independent manner. J. Biol. Chem., 1997, 272, 27224-27229. Sun, J.; Blaskovich, M.A.; Knowles, D.; Qian, Y.; Ohkanda, J.; Bailey, R.D.; Hamilton, A.D.; Sebti, S.M. Antitumor efficacy of a novel class of non-thiol-containing peptidomimetic inhibitors of farnesyltransferase and geranylgeranyltransferase I: combination therapy with the cytotoxic agents cisplatin, taxol, and gemcitabine. Cancer Res., 1999, 59, 4919-4926.

Structural Analysis of FTase Inhibitors [76] [77]

[78]

[79]

[80]

[81]

[82]

[83] [84]

[85]

[86]

[87]

[88]

[89]

[90]

[91]

Garcia, A.M.; Rowell, C.; Ackerman, K.; Kowalczyk, J.J.; Lewis, M.D. Peptidomimetic inhibitors of Ras farnesylation and function in whole cells. J. Biol Chem., 1993, 268, 18415-18418. Vogt, A.; Qian, Y.; Blaskovich, M.A.; Fossum, R.D.; Hamilton, A.D.; Sebti, S.M. A non-peptide mimetic of Ras-CAAX: Selective inhibition of farnesyltransferase and ras processing. J. Biol. Chem., 1995, 270, 660-664. Miguel, K.; Pradines, A.; Sun, J.; Hamilton, A.D.; Sebti, S.M.; Favre, G. GGTI-298 induces G0-G1 block and apoptosis whereas FTI-277 causes G2-M enrichment in A549 cells. Cancer Res., 1997, 57, 1846-1850. Sun, J.; Qian, Y.; Hamilton, A.D.; Sebti, S.M. Both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for inhibition of oncogenic K-Ras prenylation but each alone is sufficient to suppress human tumor growth in nude mouse xenografts. Oncogene, 1998, 16, 1467-1473. Kohl, N.E.; Wilson, F.R.; Mosser, S.D.; Giuliani, E.; deSolms, S.J.; Conner, M.W.; Anthony, N.J.; Holtz, W.J.; Gomez, R.P.; Lee, T.J.; Smith, R.L.; Graham, S.L.; Hartman, G.; Gibbs, J.B.; Oliff, A. Protein farnesyltransferase inhibitors block the growth of rasdependent tumors in nude mice. Proc. Natl. Acad. Sci. USA, 1994, 91, 9141-9145. Kohl, N.E.; Omer, C.A.; Conner, M.W.; Anthony, N.J.; Davide, J.P.; deSolms, S.J.; Guiliani, E.A.; Gomez, R.P.; Graham, S.L.; Hamilton, K.; Handt, L.K.; Hartman, G.D.; Koblan, K.S.; Kral, A.M.; Miller, P.J.; Mosser, S.O.; O’Neill, T.J.; Rands, E.; Schaber, M.D.; Gibb, J.B.; Oliff, A. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nat. Med., 1995, 1, 792-797. Qiao, Y.; Gao, J.; Qiu, J.; Wu, L.; Guo, F.; Lo, K.K.W.; Li, D. Design, synthesis, and characterization of piperazinedione-based dual protein inhibitors for both farnesyltransferase and geranylgeranyltransferase-I. Eur. J. Med. Chem., 2011, 46, 2264-2273. Bell, I.M. Inhibitors of protein prenylation 2000. Expert Opin. Ther. Pat., 2000, 10, 1813-1831. Sebti, S.M.; Hamilton, A.D. Farnesyltransferase and geranylgeranyltransferase I inhibitors in cancer therapy: important mechanistic and bench to bedside issues. Expert Opin. Invest. Drugs, 2000, 9, 2767-2782. Wang, L.; Wang, G.T.; Wang, X.; Tong, Y.; Sullivan, G.; Park, D.; Leonard, N.M.; Li, Q.; Cohen, J.; Gu, W.Z.; Zhang, H.; Bauch, J.L.; Jakob, C.G., Hutchins, C.W.; Stoll, V.S.; Marsh, K.; Rosenberg, S.H.; Sham, H.L.; Lin, N.H. Design, synthesis, and biological activity of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4yl)methyl]benzonitriles as potent and selective farnesyltransferase inhibitors. J. Med. Chem., 2004, 47, 612-626. Hunt, J.T.; Lee, V.G.; Leftheris, K.; Seizinger, B.; Carboni, J.; Mabus, J.; Ricca, C.; Yan, N.; Manne, V. Potent, cell active, nonthiol tetrapeptide inhibitors of farnesyltransferase. J. Med. Chem., 1996, 39, 353-358. Bohm, M.; Mitsch, A.; Wißner, P.; Sattler, I.; Schlitzer, M. Exploration of novel aryl binding sites of farnesyltransferase using molecular modeling and benzophenone-based farnesyltransferase inhibitors. J. Med. Chem., 2001, 44, 3117-3124. O`Connor, S.J.; Barr, K.J.; Wang, L.; Sorensen, B.K.; Tasker, A.S.; Sham, H.; Ng, A.C.; Cohen, J.; Devine, E.; Cherian, S.; Saeed, B.; Zhang, H.; Lee, J.Y.; Warner, R.; Tahir, S.; Kovar, P.; Ewing, P.; Alder, J.; Mitten, M.; Leal, J.; Marsh, K.; Bauch, J.; Hoffman, D.J.; Sebti, S.M.; Rosenberg, S.H. Second generation peptidomimetic inhibitors of protein farnesyltransferase demonstrating improved cellular potency and significant in vivo efficacy. J. Med. Chem., 1999, 42, 3701-3710. Augeri, D.J.; Janowick, D.; Kalvin, D.; Sullivan, G.; Larsen, J.; Dickman, D.; Ding, H.; Cohen, J.; Lee, J.; Warner, R.; Kovar, P.; Cherian, S.; Saeed, B.; Zhang, H.; Tahir, S.; Ng, S.-C.; Sham, H.; Rosenberg, S.H. Potent and orally bioavailable noncysteinecontaining inhibitors of protein farnesyltransferase. Bioorg. Med. Chem. Lett., 1999, 9, 1069-1074. Mitsch, A.; Wißner, P.; Silber, K.; Haebel, P.; Sattler, I.; Klebe, G.; Schlitzer, M. Non-thiol farnesyltransferase inhibitors: N-(4tolylacetylamino-3-benzoylphenyl)-3-arylfurylacrylic acid amides. Bioorg. Med. Chem., 2004, 12, 4585-4600. Schlitzera, M.; Sattler, I., Non-thiol farnesyltransferase inhibitors: the concept of benzophenone-based bisubstrate analogue farnesyltransferase inhibitors. Eur. J. Med. Chem., 2000, 35, 721-726.

Current Medicinal Chemistry, 2013, Vol. 20, No. 1 [92] [93] [94] [95] [96] [97]

[98]

[99] [100]

[101]

[102]

[103]

[104]

[105]

[106]

[107]

[108]

31

Schlitzer, M. Structure based design of benzophenone-based nonthiol farnesyltransferase inhibitors. Curr. Pharm. Des., 2002, 8, 1713-1722. Patel, D.V.; Patel, M.M.; Robinson, S.S.; Gordon, E.M. Phenol based tripeptide inhibitors of ras farnesyl protein transferase. Bioorg. Med. Chem. Lett., 1994, 4, 1883-1888. Schlitzer, M.; Sattler, I. Non-thiol farnesyltransferase inhibitors: the concept of benzophenone-based bisubstrate analogue farnesyltransferase inhibitors. Eur. J. Med. Chem., 2000, 35, 721-726. Tschantz, W.R.; Furfine, E.S.; Casey, P.J. Substrate binding is required for release of product from mammalian protein farnesyltransferase. J. Biol. Chem., 1997, 272, 9989-9993. Belei, D.; Dumea, C.; Samson, A.; Farce, A.; Dubois, J.; Bîcu, E.; Ghinet, A. New farnesyltransferase inhibitors in the phenothiazine series. Bioorg. Med. Chem. Lett., 2012, 22, 4517-4522. Baciu-Atudosie, L.; Ghinet, A.; Farce, A.; Dubois, J.; Belei, D,; Bicu, E. Synthesis and biological evaluation of new phenothiazine derivatives bearing a pyrazole unit as protein farnesyltransferase inhibitors. Bioorg. Med. Chem. Lett., 2012, 22, 6896-6902. Abuhaie, C.M.; Ghinet, A.; Farce, A.; Dubois, J.; Gautret, P.; Rigo, B.; Belei, D.; Bîcu, E. Synthesis and biological evaluation of a new series of phenothiazine-containing protein farnesyltransferase inhibitors. Eur. J. Med. Chem., 2013, 59, 101-110. Driggers, E.M.; Hale, S.P.; Lee, J.; Terrett, N.K. The exploration of macrocycles for drug discovery-an underexploited structural class. Nat Rev. Drug Discov., 2008, 7, 608-624. Chen, K.X.; Njoroge, F.G,: Arasappan, A.; Venkatraman, S.; Vibulbhan, B.; Yang, W.; Parekh, T.N.; Pichardo, J.; Prongay, A.; Cheng, K.C.; Butkiewicz, N.; Yao, N.; Madison, V.; Girijavallabhan, V. Novel potent hepatitis C virus NS3 serine protease inhibitors derived from prolinebased macrocycles. J. Med. Chem., 2006, 49, 995-1005. Bell, I. M.; Gallicchio, S.N.; Abrams, M.; Beese, L.S.; Beshore, D.C.; Bhimnathwala, H.; Bogusky, M.J.; Buser, C.A.; Culberson, J.C.; Davide, J.; Ellis-Hutchings, M.; Fernandes, C.; Gibbs, J.B.; Graham, S.L.; Hamilton, K.A.; Hartman, G.D.; Heimbrook, D.C.; Homnick, C.F.; Huber, H.E.; Huff, J.R.; Kassahun, K.; Koblan, K.S.; Kohl, N.E.; Lobell, R.B.; Lynch, J.J. Jr.; Robinson, R.; Rodrigues, A.D.; Taylor, J.S.; Walsh, E.S.; Williams, T.M.; Zartman, C.B. 3-Aminopyrrolidinones farnesyltransferase inhibitors: design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency. J. Med. Chem., 2002, 45, 2388-2409. Moasser, M.M.; Sepp-Lorenzino, L.; Kohl, N.E.; Oliff, A.; Balog, A.; Su, D.S.; Danishefsky, S.J.; Rosen, N. Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones. Proc. Natl. Acad. Sci. USA, 1998, 95, 1369-1374. Marcus, A.I.; O'Brate, A.M.; Buey, R.M.; Zhou, J.; Thomas, S.; Khuri, F.R.; Andreu, J.M.; Diaz, F.; Giannakakou, P. Farnesyltransferase inhibitors reverse taxane resistance. Cancer Res., 2006, 66, 8838-8846. Adjei, A.A.; Davis, J.N.; Bruzek, L.M.; Erlichman, C.; Kaufmann, S.H. Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines. Clin. Cancer Res., 2001, 7, 1438-1445. Siegel-Lakhai, W.S.; Crul, M.; Zhang, S.; Sparidans, R.W.; Pluim, D.; Howes, A.; Solanki, B.; Beijnen, J.H.; Schellens, J.H. Phase I and pharmacological study of the farnesyltransferase inhibitor tipifarnib (Zarnestra®, R115777) in combination with gemcitabine and cisplatin in patients with advanced solid tumors. Br. J. Cancer, 2005, 93, 1222-1229. Mackay, H.J.; Hoekstra, R.; Eskens, F.A.L.M.; Loos, W.J.; Crawford, D.; Voi, M.; Van Vreckem, A.; Evans, T.R.J.; Verweij, J. A phase I pharmacokinetic and pharmacodynamic study of the farnesyl transferase inhibitor BMS-214662 in combination with cisplatin in patients with advanced solid tumors. Clin. Cancer Res., 2004, 10, 2636-2644. Doisneau-Sixou, S.F.; Cestac, P.; Faye, J.C.; Favre, G.; Sutherland, R.L. Additive effects of tamoxifen and the farnesyl transferase inhibitor FTI-277 on inhibition of MCF-7 breast cancer cell-cycle progression. Int. J. Cancer, 2003, 106, 789-798. Ellis, C.A.; Vos, M.D.; Wickline, M.; Riley, C.; Vallecorsa, T.; Telford, W.G.; Zujewski, J.; Clark, G.J. Tamoxifen and the farnesyl transferase inhibitor FTI-2777 synergise to inhibit growth in estrogen receptor positive breast tumor cell lines. Breast Cancer Res. Treat., 2003, 78, 59-67.

32 Current Medicinal Chemistry, 2013, Vol. 20, No. 1 [109]

[110]

[111]

[112]

[113]

[114]

[115]

[116]

[117] [118]

[119]

[120] [121]

[122]

[123] [124]

Dalenc, F.; Giamarchi, C.; Petit, M.; Poirot, M.; Favre, G.; Faye, J.C. Farnesyltransferase inhibitor R115,777 enhances tamoxifen inhibition of MCF-7 cell growth through estrogen receptor dependent and independent pathways. Breast Cancer Res., 2005, 7, R1159-R1167. Russo, P.; Ottoboni, C.; Malacarne, D.; Crippa, A.; Riou, J.F.; O'Connor, P.M. Nonpeptidomimetic farnesyltransferase inhibitor RPR-115135 increases cytotoxicity of 5-fluorouracil: Role of p53. J. Pharmacol. Exp. Ther., 2002, 300, 220-226. Russo, P.; Malacarne, D.; Falugi, C.; Trombino, S.; O'Connor, P.M. RPR-115135, a farnesyltransferase inhibitor, increases 5-FU- cytotoxicity in ten human colon cancer cell lines: role of p53. Int. J. Cancer, 2002, 100, 266-275. Edamatsu, H.; Gau, C.L.; Nemoto, T.; Guo, L.; Tamanoi, F. Cdk inhibitors, roscovitine and olomoucine synergize with farnesyltransferase inhibitor (FTI) to induce efficient apoptosis of human cancer cell lines. Oncogene, 2000, 19, 3059-3068. Brassard, D.L.; English, J.M.; Malkowski, M.; Kirschmeier, P.; Nagabhushan, T.L.; Bishop, W.R. Inhibitors of farnesyl protein transferase and MEK1,2 induce apoptosis in fibroblasts transformed with farnesylated but not geranylgeranylated H-Ras. Exp. Cell Res., 2002, 273, 138-146. Patnaik, A.; Eckhardt, S.G.; Izbicka, E.; Rybak, M.; McCreery, H.; Davidson, K.; Hammond, L.; Mori, M.; Terada, K.; Bol, K.; Gentner, L.; Rowinsky, E. Administration of biologically and clinically relevant doses of the farnesyltransferase inhibitor R115777 and gemcitabine are feasible without pharmacokinetic (PK) interactions: A phase I and PK study (Proceedings of the 11th NCIEORTC Symposium on New Drugs in Cancer Therapy). Clin. Cancer Res., 2000, 6, 4517S (Abstract 257). Patnaik, A.; Eckhardt, S.G.; Izbicka, E.; Tolcher, A.A.; Hammond, L.A.; Takimoto, C.H.; Schwartz, G.; McCreery, H.; Goetz, A.; Mori, M.; Terada, K.; Gentner, L.; Rybak, M.E.; Richards, H.; Zhang, S.; Rowinsky, E.K. A phase I, pharmacokinetic, and biological study of the farnesyltransferase inhibitor tipifarnib in combination with gemcitabine in patients with advanced malignancies. Clin. Cancer Res., 2003, 9, 4761-7471. Theodore, C.; Geoffrois, L.; Vermorken, J.B.; Caponigro, F.; Fiedler, W.; Chollet, P.; Ravaud, A.; Peters, G.J.; de Balincourt, C.; Lacombe, D.; Fumoleau, P. Multicentre EORTC study 16997: feasibility and phase II trial of farnesyl transferase inhibitor & gemcitabine combination in salvage treatment of advanced urothelial tract cancers. Eur. J. Cancer, 2005, 41, 1150-1157. Brunner, T.B.; Gupta, A.K.; Shi, Y.; Hahn, S.M.; Muschel, R.J.; McKenna, W.G.; Bernhard, E.J. Farnesyltransferase inhibitors as radiation sensitizers. Int. J. Radiat. Biol., 2003, 79, 569-576. Hahn, S.M.; Kiel, K.; Morrison, B.W.; Mohiuddin, M.; Delaney, T.F.; Smith, D.; Brown, R.; Pramanik, B.; Deutsch, P.; Bernhard, E.; Muschel, R.; McKenna, G. Phase I trial of farnesyl protein transferase inhibitor with L-788,123 in combination with radiotherapy. Clin. Cancer Res., 2000, 6, 4481S. Zujewski, J.; Horak, I.D.; Bol, C.J.; Woestenborghs, R.; Bowden, C.; End, D.W.; Piotrovsky, V.K.; Chiao, J.; Belly, R.T.; Todd, A.; Kopp, W.C.; Kohler, D.R.; Chow, C.; Noone, M.; Hakim, F.T.; Larkin, G.; Gress, R.E.; Nussenblatt, R.B.; Kremer, A.B.; Cowan, K.H. Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer. J. Clin. Oncol., 2000, 18, 927-941. Venet, M.; End, D.; Angibaud, P. Farnesyl protein transferase inhibitor ZARNESTRATM R115777 – History of a discovery. Curr. Topics Med. Chem., 2003, 3, 1095-1102. Li, Q.; Wang, G.T.; Li, T.; Gwaltney, S.L. II, Woods, K.W.; Claiborne, A.; Wang, X.; Gu, W.; Cohen, J.; Stoll, V.S.; Hutchins, C.; Frost, D.; Rosenberg, S.H.; Sham, H.L. Synthesis and activity of 1aryl-10-imidazolyl methyl ethers as non-thiol farnesyltransferase inhibitors. Bioorg. Med. Chem. Lett., 2004, 14, 5371-5376. Lin, N.H.; Wang, L.; Wang, X.; Wang, G.T.; Cohen, J.; Gu, W.Z.; Zhang, H.; Rosenberg, S.H.; Sham, H.L. Synthesis and biological evaluation of 1-benzyl-5-(3-biphenyl-2-yl-propyl)-1H-imidazole as novel farnesyltransferase inhibitor. Bioorg. Med. Chem. Lett., 2004, 14, 5057-5062. Seifert, M.H.J.; Wolf, K.; Vitt, D. Virtual high-throughput in silico screening. Biosilico, 2003, 1, 143-149. Manly, C.J.; Louise-May, S.; Hammer, J.D. The impact of informatics and computational chemistry on synthesis and screening. Drug Discov. Today, 2001, 6, 1101-1110.

Moorthy et al. [125] [126]

[127]

[128] [129] [130] [131]

[132]

[133]

[134]

[135]

[136] [137] [138]

[139] [140] [141]

[142]

[143] [144]

Bleicher, K.H.; Böhm, H.J.; Müller, K.; Alanine, A.I. Hit and lead generation: beyond high-throughput screening. Nat. Rev. Drug Discov., 2003, 2, 369-378. Moorthy, N.S.H.N.; Ramos, M.J.; Fernandes, P.A. Structural analysis of -glucosidase inhibitors by validated QSAR models using topological and hydrophobicity based descriptors. Chemom. Intell. Lab Sys., 2011, 109, 101-112. Moorthy, N.S.H.N.; Cerqueira, N.S.; Ramos, M.J.; Fernandes, P.A. QSAR analysis of 2-benzoxazolyl hydrazone derivatives for anticancer activity and its possible target prediction. Med. Chem. Res., 2012, 21, 133-144. Sousa, S.F.; Fernandes, P.A.; Ramos, M.J. Unraveling the mechanism of the farnesyltransferase enzyme. J. Biol. Inorg. Chem., 2005, 10, 3-10. Puntambekar, D.; Giridhar, R.; Yadav, M.R. 3D-QSAR studies of farnesyltransferase inhibitors: A comparative molecular field analysis approach. Bioorg. Med. Chem. Lett., 2006, 16, 1821-1827. Vaidya, M.; Weigt, M.; Wiese, M. 3D-QSAR with the aid of pharmacophore search and docking-based alignments for farnesyltransferase inhibitors. Eur. J. Med. Chem., 2009, 44, 4070-4082. Li, Q.; Li, T.; Woods, K.W.; Gu, W.Z.; Cohen, J.; Stoll, V.S.; Galicia, T.; Hutchins, C.; Frost, D.; Rosenberg, S.H.; Sham, H.L. Benzimidazolones and indoles as non-thiol farnesyltransferase inhibitors based on tipifarnib scaffold: synthesis and activity. Bioorg. Med. Chem. Lett., 2005, 15, 2918-2922. Xie, A.; Odde, S.; Prasanna, S.; Doerksen, R.J. Imidazolecontaining farnesyltransferase inhibitors: 3D quantitative structure– activity relationships and molecular docking. J. Comput. Aided Mol. Des., 2009, 23, 431-448. Wang, G.T.; Wang, X.; Wang, W.; Hasvold, L.A.; Sullivan, G.; Hutchins, C.W.; O`Conner, S.; Gentiles, R.; Sowin, T.; Cohen, J.; Gu, W.Z.; Zhang, H.; Rosenberg, S.H.; Sham, H.L. Design and synthesis of o-trifluoromethylbiphenyl substituted 2-aminonicotinonitriles as inhibitors of farnesyltransferase. Bioorg. Med. Chem. Lett., 2005, 15, 153-158. Equbal, T.; Silakari, O.; Ravikumar, M. Three–dimensional quantitative structure–activity relationship (3D–QSAR) studies of various ether analogues of farnesyltransferase inhibitors. Internet Electronic J. Mol. Des., 2007, 6, 237-252. Perez Gonzalez, M.; Caballero, J.; Tundidor-Camba, A.; Helguera, A.M.; Fernandez, M. Modeling of farnesyltransferase inhibition by some thiol and non-thiol peptidomimetic inhibitors using genetic neural networks and RDF approaches. Bioorg. Med. Chem., 2006, 14, 200-213. Gasteiger, J.; Zupan, Neural networks in chemistry. J. Angew. Chem., Int. Ed. Engl., 1993, 32, 503-527. Zupan, J.; Gasteiger, J. Neural networks in chemistry and drug design, Wiley-VCH, Weinheim, 1999. Mitsch, A.; Bohm, M.; Wißner, P.; Sattler, I.; Schlitzer, M. Nonthiol farnesyltransferase inhibitors: utilization of an aryl binding site by 5-arylacryloylaminobenzophenones. Bioorg. Med. Chem., 2002, 10, 2657-2662. Sakowski, J.; Sattler, I.; Schlitzer, M. Non-thiol farnesyltransferase inhibitors: N-(4-Acylamino-3-benzoylphenyl)-4-nitrocinnamic acid amides. Bioorg. Med. Chem., 2002, 10, 233-239. Equbal, T.; Silakari, O.; Rambabu. G.; Ravikumar, M. Pharmacophore mapping of diverse classes of farnesyltransferase inhibitors. Bioorg. Med. Chem. Lett., 2007, 17, 1594-1600. Tanaka, R.; Rubio, A.; Harn, N.K.; Gernert, D.; Grese, T.A.; Eishima, J.; Hara, M.; Yoda, N.; Ohashi, R.; Kuwabara, T.; Soga, S.; Akinaga, S.; Nara S.; Kand, Y. Design and synthesis of piperidine farnesyltransferase inhibitors with reduced glucuronidation potential. Bioorg. Med. Chem., 2007, 15, 1363-1382. Asoh, K.; Kohchi, M.; Hyoudoh, I.; Ohtsuka, T.; Masubuchi, M.; Kawasaki, K.; Ebiike, H.; Shiratori, Y.; Fukami, T.A.; Kondoh, O.; Tsukaguchi, T.; Ishii, N.; Aoki, Y.; Shimma, N.; Sakaitani, M. Synthesis and structure–activity relationships of novel benzofuran farnesyltransferase inhibitors. Bioorg. Med. Chem. Lett., 2009, 19, 1753-1757. Moorthy, N.S.H.N.; Sousa, S.F.; Ramos, M.J.; Fernandes, P.A. Structural feature study of benzofuran derivatives as farnesyltransferase inhibitors. J. Enz. Inhibit. Med. Chem., 2011, 26, 777-791. End, D.W.; Smets, G.; Todd, A.V. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res., 2001, 61, 131-137.

Structural Analysis of FTase Inhibitors [145] [146]

[147]

[148]

[149]

[150]

[151]

[152]

[153] [154]

[155] [156] [157]

[158]

[159]

[160]

[161]

[162]

Cox, A.D.; Der, C.J. Farnesyltransferase inhibitors: promises and realities. Curr. Opin. Pharmacol., 2002, 2, 388-393. Silva, C.H.T.P.; Silva, V.B.; Resende, J.; Rodrigues, P.F.; Bononi, F.C.; Benevenuto, C.G.; Taft, C.A. Computer-aided drug design and ADMET predictions for identification and evaluation of novel potential farnesyltransferase inhibitors in cancer therapy. J. Mol. Graph. Model., 2010, 28, 513-523. Ganguly, A.K.; Doll, R.J.; Girijavallabhan, V.M. Farnesyl protein transferase inhibition: A novel approach to anti-tumor therapy. The discovery and development of SCH 66336. Curr. Med. Chem., 2001, 8, 1419-1436. Njoroge, F.G.; Vibulbhan, B.; Pinto, P.; Strickland, C.L.; Bishop, W.R.; Kirschmeir, P.; Girijavallabhan, V.; Ganguly, A.K. Trihalobenzocycloheptapyridine analogues of SCH 66336 as potent inhibitors of farnesyl protein transferase. Bioorg. Med. Chem., 2003, 11, 139-143. Polley, M.J.; Winkler, D.A.; Burden, F.R. Broad-based quantitative structure-activity relationship modeling of potency and selectivity of farnesyltransferase inhibitors using a Bayesian regularized neural network. J. Med. Chem., 2004, 47, 6230-6238. Fernandez, M.; Tundidor-Camba, A.; Caballero, J.M. 2D autocorrelation modeling of the activity of trihalobenzocycloheptapyridine analogues as farnesyl protein transferase inhibitors. Mol. Simulat., 2005, 31, 575-584. Strickland, C.L.; Weber, P.T.; Windsor, W.T.; Wu, Z.; Le, H.V.; Albanese, M.M.; Alvarez, C.S.; Cesarz, D.; del Rosario, J.; Deskus, J.; Mallams, A.K.; Njoroge, F.G.; Piwinski, J.J.; Remiszewski, S.; Rossman, R.R.; Taveras, A.G.; Vibulbhan, B.V.; Doll, R.J.; Girijavallabhan, V.M.; Ganguly, A.K. Tricyclic farnesyl protein transferase inhibitors: Crystallographic and calorimetric studies of structure–activity relationships. J. Med. Chem., 1999, 42, 2125-2135. Kwon, B M.; Lee, S.H.,; Cho, Y.K.; Bok, S.H.; So, S.H.; Youn, M.R.; Chang, S.I. Synthesis and biological activity of cinnamaldehyde as angiogenesis inhibitors. Bioorg. Med. Chem. Lett., 1997, 7, 2473-2476. Sung, N.D.; Cho, Y.K.; Kwon, B.M.; Hyun, K.H.; Kim, C.K. 3D QSAR studies on cinnamaldehyde analogues as farnesyl protein transferase inhibitors. Arch. Pharm. Res., 2004, 27, 1001-1008. Soung, M.G.; Kim, J.H.; Kwon, B.M.; Sung, N.D. Synthesis and ligand based 3D-QSAR of 2,3-bis-benzylidenesuccinaldehyde derivatives as new class potent FPTase inhibitor, and prediction of active molecules. Bull. Korean Chem. Soc., 2010, 31, 1355-1360. Burden, F.R.; Winkler, D.A. Robust QSAR models using Bayesian regularized neural networks. J. Med. Chem., 1999, 42, 3183-3187. Burden, F.R. Using artificial neural networks to predict biological activity from simple molecular structure considerations. Quant. Struct.-Act. Relat., 1996, 15, 7-11. Bishop, W.R.; Bond, R.; Petrin, J.; Wang, L.; Patton, R.; Doll, R.; Njoroge, G.; Catino, J.; Schwartz, J.; Windsor, W.; Sayto, R.; Schwartz, J.; Carr, D.; James, L.; Kirschmeier, P. Novel tricyclic inhibitors of farnesyl protein transferase. J. Biol. Chem., 1995, 270, 30611-30618. Mallams, A.K.; Njoroge, F.G.; Doll, R.J.; Snow, M.E.; Kaminski, J.J.; Rossman, R.; Vibulbhan, B.; Bishop, W.R.; Kirschmeier, P.; Liu, M.; Bryant, M.S.; Alvarez, C.; Carr, D.; James, L.; King, I.; Li, Z.; Lin, C.-C.; Nardo, J.; Petrin, J.; Remiszewski, S.; Taveras, A.; Wang, S.; Wong, J.; Catino, J.; Girijavallabhan, V.; Ganguly, A.K. Antitumor 8- chlorobenzocycloheptapyridines: A new class of selective, nonpeptidic, nonsulfhydryl inhibitors of ras farnesylation. Bioorg. Med. Chem., 1997, 5, 93-99. Njoroge, F.G.; Doll, R.J.; Vibulbhan, B.; Alvarez, C.; Bishop, W.R.; Petrin, J.; Kirschmeier, P.; Carruthers, N.I.; Wong, J.K.; Albanese, M.M.; Piwinski, J.J.; Catino, J.; Girijavallabhan, V.; Ganguly, A.K. Discovery of novel nonpeptide tricyclic inhibitors of ras farnesylation. Bioorg. Med. Chem., 1997, 5, 101-114. Rane, D.F.; Pike, R.E.; Puar, M.S.; Wright, J.J.; McPhail, A.T. A novel synthesis of cis-1-[[6-chloro-3-[(2-chloro-3-thienyl)methoxy]-2, 3-dihydrobenzo[b]thien-2-yl]methyl]-1H-imidazole. A new class of azole antifungal agents. Tetrahedron, 1988, 44, 23972402. Kaminski, J.J.; Rane, D.F.; Snow, M.E.; Weber, L.; Rothofsky, M.L.; Anderson, S.D.; Lin, S.L. Identification of novel farnesyl protein transferase inhibitors using three-dimensional database searching methods. J. Med. Chem., 1997, 40, 4103-4112. Giraud, E.; Luttmann, C.; Lavelle, F.; Riou, J.F.; Mailliet, P.; Laoui, A. Multivariate data analysis using D-optimal designs, par-

Current Medicinal Chemistry, 2013, Vol. 20, No. 1

[163]

[164]

[165]

[166] [167]

[168]

[169]

[170]

[171]

[172]

[173]

[174]

[175]

[176]

[177]

[178] [179]

[180]

33

tial least squares, and response surface modeling: A directional approach for the analysis of farnesyltransferase inhibitors. J. Med. Chem., 2000, 43, 1807-1816. Xie, A.; Clark, S.R.; Prasanna, S.; Doerksen, R.J. Threedimensional quantitative structure–farnesyltransferase inhibition analysis for some diaminobenzophenones. J. Enz. Inhib. Med. Chem., 2009, 24, 1220-1228. Gaurav, A.; Gautam, V.; Singh, R. Exploring the structure activity relationships of imidazole containing tetrahydrobenzodiazepines as farnesyltransferase inhibitors: A QSAR study. Lett. Drug Des. Discov., 2011, 8, 506-515. Shayanfar, A.; Ghasemi, S.; Soltani, S.; Asadpour-Zeynali, K.; Doerksen, R.J.; Jouyban, A. Quantitative structure-activity relationships of imidazole-containing farnesyltransferase inhibitors using different chemometric methods. Med. Chem., 2013, 9, 434-448. Lethu, S.; Ginisty, M.; Bosc, D.; Dubois, J. Discovery of a new class of protein farnesyltransferase inhibitors in the arylthiophene series. J. Med. Chem., 2009, 52, 6205-6208. Moorthy, N.S.H.N.; Sousa, S.F.; Ramos, M.J.; Fernandes, P.A. In silico-based structural analysis of arylthiophene derivatives for FTase inhibitory activity, hERG, and other toxic effects. J. Biomol. Screen., 2011, 16, 1037-1046. Chaurasia, S.; Srivastava, A.K.; Nath, A.; Srivastava, M.K.; Pandey, A. Quantitative structure activity relationship studies on a series of tetrahydroquinoline-based farnesyltransferase inhibitors. Oxid. Commun., 2007, 30, 778-787. Bendale, P.; Olepu, S.; Suryadevara, P.K.; Bulbule, V.; Rivas, K.; Nallan, L.; Smart, B.; Yokoyama, K.; Ankala, S.; Pendyala, P.R.; Floyd, D.; Lombardo, L.J.; Williams, D.K.; Buckner, F.S.; Chakrabarti, D.; Verlinde, C.L.; Van Voorhis, W.C.; Gelb, M.H. Second generation tetrahydroquinoline-based protein farnesyltransferase inhibitors as antimalarials. J. Med. Chem., 2007, 50, 4585-4605. Wiesner, J.; Mitsch, A.; Wißner, P.; Jomaa, H.; Schlitzer, M. Structure-activity relationships of novel anti-malarial agents. Part 2: cinnamic acid derivatives. Bioorg. Med. Chem. Lett., 2001, 11, 423424. Wiesner, J.; Kettler, K.; Jomaa, H.; Schlitzer, M. Structure-activity relationships of novel anti-malarial agents. Part 3: N-(4-acylamino3-benzoylphenyl)-4-propoxycinnamic acid amides. Bioorg. Med. Chem. Lett., 2002, 12, 543-545. Wiesner, J.; Mitsch, A.; Wißner, P.; Kramer, O.; Jomaa, H.; Schlitzer, M. Structure-activity relationships of novel anti-malarial agents. Part 4: N-(3-benzoyl-4-tolylacetylaminophenyl)-3-(5-aryl2-furyl)acrylic acid amides. Bioorg. Med. Chem. Lett., 2002, 12, 2681-2683. Wiesner, J.; Kettler, K.; Sakowski, J.; Ortmann, R.; Jomaa, H.; Schlitzer, M. Structure-activity relationships of novel anti-malarial agents: part 5. N-(4-acylamino-3-benzoylphenyl)-[5-(4nitrophenyl)-2-furyl]acrylic acid amides. Bioorg. Med. Chem. Lett., 2003, 13, 361-363. Wiesner, J.; Fucik, K.; Kettler, K.; Sakowski, J.; Ortmann, R.; Jomaa, H.; Schlitzer, M. Structure-activity relationships of novel anti-malarial agents. Part 6: N-(4-arylpropionylamino-3benzoylphenyl)-[5-(4-nitrophenyl)-2-furyl]acrylic acid amides. Bioorg. Med. Chem. Lett., 2003, 13, 1539-1541. Wiesner, J.; Mitsch, A.; Jomaa, H.; Schlitzer, M. Structure-activity relationships of novel anti-malarial agents. Part 7: N-(3-benzoyl-4tolylacetylaminophenyl)-3-(5-aryl-2-furyl)acrylic acid amides with polar moieties. Bioorg. Med. Chem. Lett., 2003, 13, 2159-2161. Cormanich, R.A.; Freitas, M.P.; Rittner, R. 2D chemical drawings correlate to bioactivities: MIA-QSAR modelling of antimalarial activities of 2,5-diaminobenzophenone derivatives. J. Braz. Chem. Soc., 2011, 22, 637-642. Deeb, O.; Alfalah, S.; Freitas, M.P.; Cunha, E.F.F.; Ramalho, T.C. Exploring MIA-QSARs for farnesyltransferase inhibitory effect of antimalarial compounds refined by docking simulations. J. Biophys. Chem., 2012, 3, 58-71. Schmitz, F.J.; Bloor, S.J. Xesto- and halenaquinone derivatives from a sponge, Adocia sp., from Truk lagoon. J. Org. Chem., 1988, 53, 3922-3925. Cao, S.; Foster, C.; Brisson, M.; Lazo, J.S.; Kingston, D.G.I. Halenaquinone and xestoquinone derivatives, inhibitors of Cdc25B phosphatase from a Xestospongia sp. Bioorg. Med. Chem., 2005, 13, 999-1003. Alvi, K.A.; Rodríguez, J.; Diaz, M.C.; Moretti, R.; Wilhelm, R.S.; Lee, R.H.; Slate, D. L.; Crews, P. Protein tyrosine kinase inhibitory

34 Current Medicinal Chemistry, 2013, Vol. 20, No. 1

[181]

[182]

[183] [184]

[185]

[186]

[187] [188] [189]

[190]

[191] [192]

[193] [194] [195] [196] [197] [198] [199] [200]

properties of planar polycyclics obtained from the marine sponge Xestospongia cf. carbonaria and from total synthesis. J. Org. Chem., 1993, 58, 4871-4880. Kobayashi, J.; Hirase, T.; Shigemori, H.; Ishibashi, M.; Bae, M.-A.; Tsuji, T.; Sasaki, T. New pentacyclic compounds from the okinawan marine sponge Xestospongia sapra. J. Nat. Prod., 1992, 55, 994-998. Kobayashi, M.; Shimizu, N.; Kyogoku, Y.; Kitagawa, I. Halenaquinol and halenaquinol sulphate, pentacyclic hydroquinones from the okinawan marine sponge Xestospongia sapra. Chem. Pharm. Bull., 1985, 33, 1305-1308. Roll, D.M.; Scheuer, P.J.; Matsumoto, G.K.; Clardy, J. Halenaquinone, a pentacyclic polyketide from a marine sponge. J. Am. Chem. Soc., 1983, 105, 6177-6178. Desoubzdanne, D.; Marcourt, L.; Raux, R.; Chevalley, S.; Dorin, D.; Doerig, C.; Valentin, A.; Ausseil, F.; Debitus, C. Alisiaquinones and alisiaquinol, dual inhibitors of Plasmodium falciparum enzyme targets from a New Caledonian deep water sponge. J. Nat. Prod., 2008, 71, 1189-1192. Longeon, A.; Copp, B.R.; Roué, M.; Dubois, J.; Valentin, A.; Petek, S.; Debitus, C.; Bourguet-Kondracki, M.L. New bioactive halenaquinone derivatives from South Pacific marine sponges of the genus Xestospongia. Bioorg. Med. Chem., 2010, 18, 6006-6011. Yonemoto, M.; Satoh, T.; Arakawa, H.; Suzuki-Takahashi, I.; Monden, Y.; Kodera, T.; Tanaka, K.; Aoyama, T.; Iwasawa, Y.; Kamei, T.; Nishimura, S.; Tomimoto, K. J-104,871, a novel farnesyltransferase inhibitor, blocks Ras farnesylation in vivo in a farnesyl pyrophosphate-competitive manner. Mol. Pharmacol., 1998, 54, 1-7. Hardin, J.; MacLeod, S.; Grigorieva, I.; Chang, R.; Barlogie, B.; Xiao, H.; Epstein, J. Interleukin-6 prevents dexamethasone induced myeloma cell death. Blood, 1994, 84, 3063-3070. Hilbert, D.M.; Kopf, M.; Mock, B.A.; Kohler, G.; Rudikoff, S. Interleukin 6 is essential for in vivo development of B lineage neoplasms. J. Exp. Med., 1995, 182, 243-248. Frassanito, M.A.; Cusmai, A.; Piccoli, C.; Dammacco, F. Manumycin inhibits farnesyltransferase and induces apoptosis of drug-resistant interleukin 6-producing myeloma cells. Br. J. Haematol., 2002, 118, 157-165. Kim, Y.S.; Kim, J.S.; Park, S.H.; Choi, S.U.; Lee, C.O.; Kim, S.K.; Kim, Y.K.; Kim, S.H.; Ryu, S.Y. Two cytotoxic sesquiterpene lactones from the leaves of Xanthium strumarium and their in vitro inhibitory activity on farnesyltransferase. Planta Med., 2003, 69, 375-377. Ancuceanu, R.V.; Istudor, V. Pharmacologically active natural compounds for lung cancer. Altern. Med. Rev. 2004, 9, 402-419. Nour, A.M.; Khalid, S.A.; Kaiser, M.; Brun, R.; Abdallah, W.E.; Schmidt, T.J. The antiprotozoal activity of sixteen asteraceae species native to Sudan and bioactivity-guided isolation of xanthanolides from Xanthium brasilicum. Planta Med., 2009, 75, 13631368. Ahmed, A.A.; Jakupovic, J.; Bohlmann, F.; Regaila, H.A.; Ahmed, A.M. Sesquiterpene lactones from Xanthium pungens. Phytochemistry, 1990, 29, 2211-2215. Cumanda, J.; Marinoni, G.; de Bernardi, M.; Vidari, G.; Vita Finzi, P. New sesquiterpenes from Xanthium catharticum. J. Nat. Prod., 1991, 54, 460-465. de Riscala, E.C.; Fortuna, M.A.; Catalan, C.A.N.; Diaz, J.G.; Herz, W. Xanthanolides and a bis-norxanthanolide from Xanthium cavanillesii. Phytochem., 1994, 35, 1588-1589. Joshi, S.P.; Rojatkar, S.R.; Nagasampagi, B.A. Antimalarial activity of Xanthium strumarium Linn. J. Med. Aromat. Plant Sci., 1997, 19, 366-368. Vasas, A.; Hohmann, J. Xanthane sesquiterpenoids: structure, synthesis and biological activity. Nat. Prod. Rep., 2011, 28, 824842. Kuo, Y.H.; Lin, B.Y. A new dinorxanthane and chromanone from the root of Tithonia diversifolia. Chem. Pharm. Bull., 1999, 47, 428-429. Matsuo, K.; Yokoe, H.; Shishido, K.; Shindo, M. Synthesis of diversifolide and structure revision. Tetrahedron Lett., 2008, 49, 4279-4281. Kwon, B.M.; Lee, S.H.; Kim, M.J.; Kim, H.K.; Kim, H.M. Isolation of farnesyltransferase inhibitors from herbal medicines. Ann. N. Y. Acad. Sci., 1999, 886, 261-264.

Moorthy et al. [201] [202] [203]

[204] [205]

[206]

[207]

[208] [209]

[210] [211]

[212] [213]

[214]

[215] [216] [217]

[218]

[219] [220]

[221]

Picman, A.K. Biological activities of sesquiterpene lactones. Biochem. Syst. Ecol., 1986, 14, 255-281. Das, M.; Chaudhuri, T.; Goswami, S.K. Studies with black tea and its constituents on leukemic cells and cell lines. J. Exp. Clin. Cancer Res., 2002, 21, 563-568. Manna, S.; Mukherjee, S.; Roy, A. Tea polyphenols can restrict benzo[a]pyrene-induced lung carcinogenesis by altered expression of p53-associated genes and H-ras, c-myc and cyclin D1. J. Nutr. Biochem., 2009, 20, 337-349. Balajee, R.; Dhana Rajan, M.S. Molecular docking and simulation studies of farnesyl transferase with the potential inhibitor Theflavin. J. Appl. Pharm. Sci., 2011, 1, 141-148. Dalsgaard, P.W.; Petersen, B.O.; Duus, J.O.; Zidorn, C.; Frisvad, J.C.; Christophersen, C.; Larsen, T.O. Atlantinone A, a meroterpenoid produced by Penicillium ribeum and several cheese associated Penicillium species. Metabolites, 2012, 2, 214-220. Shiomi, K.; Uchida, R.; Inokoshi, J.; Tanaka, H.; Iwai, Y.; Omura, S. Andrastins A-C, new protein farnesyltransferase inhibitors, produced by Penicillium sp. FO-3929. Tetrahedron Lett., 1996, 37, 1265-1268. Omura, S.; Inokoshi, J.; Uchida, R.; Shiomi, K.; Masuma, R.; Kawakubo, T.; Tanakaf, H.; Iwai, Y.; Kosemurall, S.; Yamamurall, S. Andrastins A-C, new protein farnesyltransferase inhibitors produced by penicillium sp. FO-3929. I. Producing strain, fermentation, isolation, and biological activities. J. Antibiotics, 1996, 49, 414-417. Houbraken, J.; Samson, R.A. Phylogeny of Penicillium and the segregation of Trichocomaceae into three families. Stud. Mycol., 2011, 70, 1-51. Thutewohl, M.; Kissau, L.; Popkirova, B.; Karaguni, I.M.; Nowak, T.; Bate, M.; Kuhlmann, J.; Muller, O.; Waldmann, H. Identification of mono- and bisubstrate inhibitors of protein farnesyltransferase and inducers of apoptosis from a pepticinnamin E library. Bioorg. Med. Chem., 2003, 11, 2617-2626. Sun, D. Highly stereoselective and efficient synthesis of the dopa analogue in pepticinnamin E via enantioselective hydrogenation of dehydroamino acids. Turk. J. Chem., 2010, 34, 181-186. Leonard, D.M.; Schuber, K.R.; Poulter, C.J.; Eaton, S.R.; Sawyer, T.K.; Hodges, J.C.; Su T,-Z.; Scholten, J.D.; Gowan, R.; SeboldLeopold, J.S.; Doherty, A.M. Structure-activity relationships of cysteine-lacking pentapeptide derivatives that inhibit ras farnesyltransferase. J. Med. Chem., 1997, 40, 192-200. Waldmann, H.; Thutewohl, M. Ras-farnesyltransferase-inhibitors as promising anti-tumor drugs. Topics Curr. Chem., 2000, 211, 117-130. Singh, S.B.; Jones, E.T.; Goetz, M.A.; Bills, G.F.; Nallin-Omstead, M.; Jenkins, R.G.; Lingham, R.B.; Silverman, K.C.; Gibbs, J.B. Fusidienol: A novel inhibitor of Ras farnesyl-protein transferase from Fusidiumgriseum. Tetrahedron Lett., 1994, 35, 4693-4696. Singh, S.B.; Zink, D.L.; Liesch, J M.; Ball, R.G.; Goetz, M.A.; Bolessa, E.A.; Giacobbe, R.A.; Silverman, K.C.; Bills, G.F.; Pelaez, F.; Cascales, C.; Gibbs, J.B.; Lingham, R.B. Preussomerins and deoxypreussomerins: Novel inhibitors of ras farnesyl-protein transferase. J. Org. Chem., 1994, 59, 6296-6302. Larsen, B.; Shah, D. Candida isolates of yeast produce a gliotoxinlike substance. Mycopathologia, 1991, 116, 203-208. Van Der Pyl, D.; Inokoshi, J.; Shiomi, K.; Yang, H.; Takeshima, H.; Omura, S. Inhibition of farnesyl protein transferse by gliotoxin and acetylgliotoxin. J. Antibiotics, 1992, 45, 1802-1805. Singh, S.B.; Zink, D.L.; Bills, G.F.; Jenkins, R.G.; Silverman, K.C.; Lingham, R.B. Cylindrol A: A novel inhibitor of ras farnesylprotein transferase from Cylindrocarpon lucidum. Tetrahed. Lett., 1995, 36, 4935-4938. Liu, C.; Barbacid, M.; Bulgar, M.; Clark, J.M.; Crosswell, A.R.; Dean, L.; Doyle, T.W.; Fernandes, P.B.; Huang, S.; Manne, V.; Pirnik, D.M.; Wells, J.S.; Meyers, E. O'-Desmethoxystreptonigrin, A novel analog of streptonigrin. J. Antibiotics, 1992, 45, 454-457. Nonomura, H. Key for classification and identification of 458 species of the streptomycetes included in ISP. J. Ferment. Technol., 1974, 52, 78-92. Lingham, R.B.; Sheo, B. Singh, Farnesyl-protein transferase: A new paradigm for cancer chemotherapy, advances in discovery and development of natural product inhibitors. Stud. Nat. Prod. Chem., 2000, 24, 403-472. Singh, S.B.; Zinc, D.L.; Liesch, J.M.; Goetz, M.A.; Jenkins, R.G.; Nallin-Omstead, M.; Silverman, K.C.; Bills, G.F.; Mosley, R.T.;

Structural Analysis of FTase Inhibitors

[222]

[223]

[224]

[225]

[226] [227] [228] [229]

[230]

[231] [232] [233]

[234]

[235] [236] [237]

[238]

[239] [240]

Gibbs, J.B.; Albers- Schonberg, G.; Lingham, R.B. Isolation and structure of Chaetomelic acids A and B from Chaetomella acutiseta: Farnesyl pyrophosphate mimic inhibitors of ras farnesylprotein transferase. Tetrahedron 1993, 49, 5917-5926. Bellesia, F.; Choi, S.R.; Felluga, F.; Fiscaletti, G.; Ghelfi, F.; Menziani, M.C.; Parsons, A.F.; Poulter, C.D.; Roncaglia, F.; Sabbatini, M.; Spinelli, D. Novel route to chaetomellic acid A and analogues: Serendipitous discovery of a more competent FTase inhibitor. Bioorg. Med. Chem., 2013, 21, 348-358. Singh, S.B.; Liesch, J.M.; Lingham, R.B.; Silverman, K.C.; Sigmund, J.M.; Goetz, M.A. Structure, chemistry, and biology of actinoplanic acids: Potent inhibitors of Ras farnesyl-protein transferase. J. Org. Chem., 1995, 60, 7896-7901. Gibbs, J.B.; Pompliano, D.L.; Mosser, S.D.; Rands, E.; Linghan, R.B.; Singh, S.B.; Scolnick, E.M.; Kohl, N.E. Selective-inhibition of farnesyl-protein transferase blocks ras processing. J. Biol. Chem., 1993, 268, 7617-7620. Dbrah, T.T.; Kaneko, T.W.; Massefski, J.; Whipple, E.B. CP-225, 917 and CP-263, 114: Novel ras farnesylation inhibitors from an unidentified fungus. 2. Structure elucidation. J. Am. Chem. Soc., 1997, 119, 1594-1598. Tomillero, A.; Moral, M.A. Gateways to clinical trials. Methods Find Exp. Clin. Pharmacol., 2010, 32, 599-620. Caponigro, F. Farnesyltransferase inhibitors: A major breakthrough in anticancer therapy? Naples, 12 April 2002. Anticancer Drugs, 2002, 13, 891-897. Caponigro, F.; Casale, M.; Bryce, J. Farnesyltransferase inhibitors in clinical development. Expert Opin. Invest. Drugs, 2003, 12, 943954. http://clinicaltrials.gov/ct2/show/NCT00354146. A phase 2 study of farnesyl transferase inhibitor (R115777, Tipifarnib) in patients with refractory or relapsed acute myeloid leukemia. Accessed on 22-04-2013. Reid, T.S.; Beese, L.S. Crystal structures of the anticancer clinical candidates R115777 (Tipifarnib) and BMS-214662 complexed with protein farnesyltransferase suggest a mechanism of FTI selectivity. Biochemistry, 2004, 43, 6877-6884. http://www.progeriaresearch.org/first-ever-progeria-treatment.html. Accessed on 25-04-2013. http://clinicaltrials.gov/ct2/show/NCT00425607. Accessed on 2504-2013. Gordona, L.B.; Kleinmana, M.E.; Millerd, D.T.; Neubergg, D.S.; Giobbie-Hurderg, A.; Gerhard-Hermani, M.; Smootj, L.B.; Gordonc,k, C.M.; Clevelandm, R.; Snydern, B.D.; Fligorp, B.; Bishopq, W.R.; Statkevichq, P.; Regenr, A.; Sonisr, A.; Rileys, S.; Ploskis, C.; Correias, A.; Quinnt, N.; Ullrichv, N.J.; Nazariano, A.; Liangd, M.J.; Huhd, S.Y.; Schwartzmang, A.; Kieranx, M.W. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson–Gilford progeria syndrome. Proc. Natl. Acad. Sci. USA, 2012, 109, 16666-16671. Bolchi, C.; Pallavicini, M.; Fumagalli, L.; Ferri, N.; Corsini, A.; Rusconi, C.; Valoti, E. New Ras CAAX mimetics: design, synthesis, antiproliferative activity, and RAS prenylation inhibition. Bioorg. Med. Chem. Lett., 2009, 19, 5500-5504. Eskens, F.A.L.M. & Stoter, G., Verweij, J. Farnesyl transferase inhibitors: current developments and future perspectives. Cancer Treat. Rev., 2000, 26, 319-332. Tsimberidou, A.M.; Chandhasin, C.; Kurzrock, R. Farnesyltransferase inhibitors: where are we now?. Expert Opin. Invest. Drugs, 2010, 19, 1569-1580. www.ClinicalTrials.gov identifier NCT00383474. Phase I combination trial, the effect of combination treatment of tipifarnib and bortezomib in patients with advanced acute leukemias. Accessed on 22-04-2013. Lancet, J.E.; Duong, V.H.; Winton, E.F.; Stuart, R.K.; Burton, M.; Zhang, S.; Cubitt, C.; Blaskovich, M.A.; Wright, J.J.; Sebti, S.; Sullivan, D.M. A phase I clinical-pharmacodynamic study of the farnesyltransferase inhibitor tipifarnib in combination with the proteasome inhibitor bortezomib in advanced acute leukemias. Clin. Cancer Res., 2011, 17, 1140-1146. http://clinicaltrialsfeeds.org/clinical-trials/results/term=FTI. Accessed on 25-04-2013. http://clinicaltrials.gov/ct2/show/NCT00038597. Phase II study of SCH66336, A farnesyltransferase inhibitor in chronic myelogenous leukemia (CML). Accessed on 22-04-2013.

Current Medicinal Chemistry, 2013, Vol. 20, No. 1 [241] [242] [243]

[244]

[245]

[246]

[247] [248]

[249] [250]

[251]

[252]

[253]

[254]

[255]

[256]

35

Rakha, P.; Gupta, A.; Dhingra, G.; Nagpal, M. Hutchinson– Gilford progeria syndrome: A review. Der Pharmacia Sinica, 2011, 2, 110-117. Peng, G.; Ren, Y.; Sun, X.; Zhou, J.; Li, D. Inhibition of farnesyltransferase reduces angiogenesis by interrupting endothelial cell migration. Biochem. Pharmacol., 2012, 83, 1374-1382. Widemann, B.C.; Arceci, R.J.; Jayaprakash, N.; Fox, E.; Zannikos, P.; Goodspeed, W.; Goodwin, A.; Wright, J.J.; Blaney, S.M.; Adamson, P.C.; Balis, F.M. Phase 1 trial and pharmacokinetic study of the farnesyl transferase inhibitor tipifarnib in children and adolescents with refractory leukemias: a report from the Children's Oncology Group. Pediatr. Blood Cancer, 2011, 56, 226-233. Pellicano, F.; Copland, M.; Jorgensen, H.G.; Mountford, J.; Leber, B.; Holyoake, T.L. BMS-214662 induces mitochondrial apoptosis in chronic myeloid leukemia (CML) stem/progenitor cells, including CD34+38- cells, through activation of protein kinase Cbeta. Blood, 2009, 114, 4186-4196. Balabanov, S.; Evans, C.A.; Abraham, S.A.; Pellicano, F.; Copland, M.; Walker, M.J.; Whetton, A.D.; Holyoake, T.L. Quantitative proteomics analysis of BMS-214662 effects on CD34 positive cells from chronic myeloid leukaemia patients. Proteomics, 2013, 13, 153-168. Lobell, R.B.; Liu, D.; Buser, C.A.; Davide, J.P.; DePuy, E.; Hamilton, K.; Koblan, K.S.; Lee, Y.; Mosser, S.; Motzel, S.L.; Abbruzzese, J.L.; Fuchs, C.S.; Rowinsky, E.K.; Rubin, E.H.; Sharma, S.; Deutsch, P.J.; Mazina, K.E.; Morrison, B.W.; Wildon, L. Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl: protein transferase and geranylgeranyl: protein transferase type-I. Mol. Cancer Ther., 2002, 1, 747-758. http://clinicaltrials.gov/show/NCT00004057?displayxml=true. Accessed on 25-04-2013. Kim, C.K.; Choi, Y.K.; Lee, H.; Ha, K.S.; Won, M.H.; Kwon, Y.G.; Kim, Y.M. The farnesyltransferase inhibitor LB42708 suppresses vascular endothelial growth factor-induced angiogenesis by inhibiting Ras-dependent mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signal pathways. Mol. Pharmacol., 2010, 78, 142-150. http://www.axonmedchem.com/product/1794lb42708.html. Accessed on 22-04-2013. Na, H.J.; Lee, S.J.; Kang, Y.C.; Cho, Y.L.; Nam, W.D.; Kim, P.K.; Ha, K.S.; Chung, H.T.; Lee, H.; Kwon, Y.G.; Koh, J.S.; Kim, Y.M. Inhibition of farnesyltransferase prevents collagen-induced arthritis by down-regulation of inflammatory gene expression through suppression of p21ras- dependent NF-B activation. J. Immunol., 2004, 173, 1276-1283. Chang, M.; Lee, S.H; Kim, H.J.; Koh, J.S.; Kim, A. Preclinical metabolism of LB42908, a novel farnesyl transferase inhibitor, and its effects on the cytochrome P450 isozyme activities. Bioorg. Med. Chem. Lett., 2012, 22, 3067-3071. Dinsmore, C.J.; Bogusky, M.J.; Culberson, J.C.; Bergman, J.M.; Homnick, C.F.; Zartman, C.B.; Mosser, S.D.; Schaber, M.D.; Robinson, R.G.; Koblan, K.S.; Huber, H.E.; Graham, S.L.; Hartman, G.D.; Huff, J.R.; Williams, T.M. Conformational restriction of flexible ligands guided by the transferred noe experiment: potent macrocyclic inhibitors of farnesyltransferase. J. Am. Chem. Soc., 2001, 123, 2107-2108. Palmioli, A.; Sacco, E.; Abraham, S.; Thomas, C.J.; Domizio, A.D.; Gioia, L.D.; Gaponenko, V.; Vanoni, M.; Peri, F. First experimental identification of Ras-inhibitor binding interface using a water-soluble Ras ligand. Bioorg. Med. Chem. Lett. 2009, 19, 4217-4222. Ganguly, A.K.; Wang, Y.S.; Pramanik, B.N.; Doll, R.J.; Snow, M.E.; Taveras, A.G.; Remiszewski, S.; Cesarz, D.; del Rosario, J.; Vibulbhan, B.; Brown, J.E.; Kirschmeier, P.; Huang, E.C.; Heimark, L.; Tsarbopoulos, A.; Girijavallabhan, V.M. Interaction of a novel GDP exchange inhibitor with the Ras protein. Biochemistry, 1998, 37, 15631-15637. Kelly, J.; Dominguez-Escrig, J.; Leung, H.Y.; Stephens, T.C.; Neal, D.E.; Davies, B.R. The prenyltransferase inhibitor AZD3409 has anti-tumor activity in preclinical models of urothelial carcinoma. Proc. Am. Assoc. Cancer Res., 2005, 46, abstract 5962 Stephens, T.C.; Wardleworth, M.J.; Matusiak, Z.S.; Ashton, S.E.; Hancox, U.J.; Bate, M.; Ferguson, R.; Boyle, T. AZD3409, a novel, oral, protein prenylation inhibitor with promising preclinical antitumor activity. Proc. Am. Assoc. Cancer Res., 2003, 44, R4870.

36 Current Medicinal Chemistry, 2013, Vol. 20, No. 1 [257]

[258]

Moorthy et al.

Song, S.Y.; Meszoely, I.M.; Coffey, R.J.; Pietenpol, J.A.; Leach, S.D. K-ras independent effects of the farnesyl transferase inhibitor L-744832 on cyclin B1/Cdc kinase activity, G2/M cell cycle progression and apoptosis in human pancreatic ductal adenocarcinoma cells. Neoplasia, 2000, 2, 261-272. Manne, V.; Yan, N.; Carboni, J.M.; Tuomari, A.V.; Ricca, C.S.; Brown, J.G.; Andahazy, M.L.; Schmidt, R.J.; Patel, D.; Zahler, R.

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[259]

Bisubstrate inhibitors of farnesyltransferase: a novel class of specific inhibitors of ras transformed cells. Oncogene, 1995, 10, 17631779. Ghinet, A; Rigo, B.; Dubois, J.; Farce, A.; Hénichart, J.-P.; Gautret, P. Discovery of ferrocene-containing farnesyltransferase inhibitors. Investigation of bulky lipophilic groups for the A2 binding site of farnesyltransferase. Med. Chem. Comm., 2012, 3, 1147-1154