Evolution of gastric bypass mimetic approaches

1 downloads 0 Views 80KB Size Report
Interest in the GLP-1R/GCGR/Y2R/Y4R tetra-agonists arose from discussions in 2012 with Qi-Ying Hu in the Global Discovery Chemistry (GDC) group. He.
The gastric bypass surgery mime1c review ar1cle (Boe8cher, BR (2017) “Gastric Bypass Surgery Mime1c Approaches” Drug Discovery Today 22, 1242-1249) summarizes our research back through the late 1990s star1ng with the discovery of the PPAR-α/γ dual agonist, cevoglitazar. The lead structure for cevoglitazar was iden1fied from a “virtual screen” carried out by Mike Sabio and T. R. Vedananda. This was the first example of a virtual screen producing a clinical candidate in Novar1s. Subsequently, Jiaping Gao carried out the in vivo screen in fa8y Zucker rats to iden1fy PPAR-α/γ dual agonists the were differen1ated from pioglitazone, i.e. had the same glycemic control of pioglitazone but with weight loss rather than weight gain. It was only much later in development that we learned this unique differen1a1on was due to 1ssue distribu1on – i.e. non-adipose 1ssue targe1ng rather than some ideal blend of PPAR-α and -γ ac1vi1es. At the 1me the dipep1dyl pep1dase-4 (DPP-4) inhibitor, vildaglip1n (Galvus), was being developed, Pei Ran (Arthur) Wang carried out combina1on studies with vildaglip1n and cevoglitazar showing addi1ve/ supra-addi1ve body weight and glycemic control efficacies. This was the first indica1on that the combina1on of GLP-1 and FGF21 had complementary effects, although at the 1me of the experiments FGF21 was rela1vely unknown and there were no publica1ons regarding its role in metabolic diseases. A]er these studies Development management made the decision in 2007, following a budget crisis, to outlicense cevoglitazar even though a 12-week clinical trial was planned, approved and recruitment underway. Even though this trial only accounted for 1-2% of the required budget savings, the trial was stopped in the middle of recruitment rather than delay or redesign the trial. Thus, cevoglitazar’s true poten1al for glycemic and body weight control was never properly explored in man. Subsequently, the vildaglip1n plus cevoglitazar combina1on results drove our interest in the GLP-1-FGF21 fusion protein once it became known that the PPAR-α ac1vity of cevoglitazar increased hepa1c expression of FGF21. The dual ac1vity fusion protein project was carried out in collabora1on with colleagues, Bernhard Geierstanger and Susan CelliA, at the Genomics Ins1tute of the Novar1s Research Founda1on (GNF) in La Jolla, CA. With Peter McNamara’s help, I was fortunate enough to spend my last year

(2012 - 2013) before re1rement at GNF helping to complete the fusion protein op1miza1on and characteriza1on before final candidate selec1on for development. While at GNF we also a8empted to iden1fy the protease responsible for inac1va1on of FGF21 based on in vivo results with GLP-1FGF21 fusion protein analogs. The iden1fica1on of fibroblast ac1va1on protein (FAP) by 4 different groups in 2016 as the protease responsible for FGF21 inac1va1on hopefully may drive renewed interest in cevoglitazar as a combina1on partner, this 1me with DPP-4/FAP dual inhibitors rather than with a DPP-4 inhibitor (vildaglip1n) as originally intended more than 10 years earlier. The increased ghrelin levels observed following cevoglitazar treatment in humans may be a compensatory response to cevoglitazar’s intes1nal PPARα activity that inhibits food intake. In addition to increasing food intake, ghrelin has cardioprotective benefits. As another bonus, it appears likely that cevoglitazar’s PPAR-γ ac1vity can drive hepa1c SR-BI expression leading

to enhanced reverse cholesterol transport and cholesterol flux. The 2016 human gene1c results from Daniel Rader’s group further support increasing SR-BI to reduce coronary heart disease.

Interest in the GLP-1R/GCGR/Y2R/Y4R tetra-agonists arose from discussions in 2012 with Qi-Ying Hu in the Global Discovery Chemistry (GDC) group. He proposed the disulfide inser1on approach as a way to both “staple” alpha helical pep1des and cross link two different pep1des. Both GLP-1R/GCGR dual agonists and Y2R/Y4R dual agonists are alpha helical pep1des and would be amenable to such modifica1ons. It was gra1fying to see that Pete Schultz’s group had been thinking along similar lines of using disulfide inser1on to “staple” a GLP-1 analog. Moreover, in 2017 his ins1tute (Calibr) entered into an agreement with Intarcia to develop stapled pep1des for combina1on with ITCA 650, Intarcia’s late stage mini-pump delivered GLP-1 therapy. This project was implemented while at GNF but unexpectedly GDC management stopped the collabora1on (even requiring Qi-Ying Hu to remove his name from the GNF proposal) without allowing the feasibility studies to proceed. Finally, the iden1fica1on in 2016 by Jens Holst’s group that a 1ssue-based protease is responsible for inac1va1on of PYY3-36 should drive research to iden1fy and develop inhibitors of this protease. The combina1on of

inhibitors of this unknown protease with DPP-4/FAP dual inhibitors and cevoglitazar should increase GLP-1, FGF21 and PYY3-36 ac1vi1es thereby providing the most effec1ve, orally available mime1cs of gastric bypass surgery. Opportuni1es in obesity and metabolic disease drug discovery have never been brighter.