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GPR40-mediated Gα12 activation by allosteric full agonists highly efficacious at potentiating glucose-stimulated insulin secretion in human islets.

GPR40-mediated Gα12 activation by allosteric full agonists highly efficacious at potentiating glucose-stimulated insulin secretion in human islets.
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Rives ML, Rady B, Swanson N, Zhao S, Qi J, Arnoult E, Bakaj I, Mancini A, Breton B, Lee PS, Player MR, Pocai A,


Rives ML, Rady B, Swanson N, Zhao S, Qi J, Arnoult E, Bakaj I, Mancini A, Breton B, Lee PS, Player MR, Pocai A, (click to view)

Rives ML, Rady B, Swanson N, Zhao S, Qi J, Arnoult E, Bakaj I, Mancini A, Breton B, Lee PS, Player MR, Pocai A,

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Molecular pharmacology 2018 03 23() pii mol.117.111369
Abstract

GPR40 is a clinically validated molecular target for the treatment of diabetes. Many GPR40 agonists have been identified to date, with the partial agonist fasiglifam (TAK-875) reaching phase III clinical trials before its development was terminated due to off-target liver toxicity. Since then, attention has shifted toward the development of full agonists that exhibit superior efficacy in preclinical models. Full agonists bind to a distinct binding site, suggesting conformational plasticity and a potential for biased agonism. Indeed, it has been suggested that alternative pharmacology may be required for meaningful efficacy. In this study, we described the discovery and characterization of Compound A, a newly identified GPR40 allosteric full agonist highly efficacious in human islets at potentiating glucose-stimulated insulin secretion. We compared Compound A-induced GPR40 activity to that induced by both fasiglifam and AM-1638, another allosteric full agonist previously reported to be highly efficacious in preclinical models, at a panel of G proteins. Compound A was a full agonist at both the Gαq and Gαi2 pathways and in contrast to fasiglifam, Compound A also induced Gα12 coupling. Compound A and AM-1638 displayed similar activity at all pathways tested. The Gα12/Gα13-mediated signaling pathway has been linked to protein kinase D activation as well as actin remodeling, well known to contribute to the release of insulin vesicles. Our data suggest that the pharmacology of GPR40 is complex and that Gα12/Gα13-mediated signaling, which may contribute to GPR40 agonists therapeutic efficacy, is a specific property of GPR40 allosteric full agonists.

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