Learn from failures and stay hopeful to GPR40, a GPCR target with robust efficacy, for therapy of metabolic disorders

Abstract

GPR40 is a class A G-protein coupled receptor (GPCR) mainly expressed in pancreas, intestine, and brain. Its endogenous ligand is long-chain fatty acids, which activate GPR40 after meal ingestion to induce secretion of incretins in the gut, including GLP-1, GIP, and PYY, the latter control appetite and glucose metabolism. For its involvement in satiety regulation and metabolic homeostasis, partial and AgoPAM (Positive Allosteric Modulation agonist) GPR40 agonists had been developed for type 2 diabetes (T2D) by many pharmaceutical companies. The proof-of-concept of GPR40 for control of hyperglycemia was achieved by clinical trials of partial GPR40 agonist, TAK-875, demonstrating a robust decrease in HbA1c (-1.12%) after chronic treatment in T2D. The development of TAK-875, however, was terminated due to liver toxicity in 2.7% patients with more than 3-fold increase of ALT in phase II and III clinical trials. Different mechanisms had since been proposed to explain the drug-induced liver injury, including acyl glucuronidation, inhibition of mitochondrial respiration and hepatobiliary transporters, ROS generation, etc. In addition, activation of GPR40 by AgoPAM agonists in pancreas was also linked to β-cell damage in rats. Notwithstanding the multiple safety concerns on the development of small-molecule GPR40 agonists for T2D, some partial and AgoPAM GPR40 agonists are still under clinical development. Here we review the most recent progress of GPR40 agonists development and the possible mechanisms of the side effects in different organs, and discuss the possibility of developing novel strategies that retain the robust efficacy of GPR40 agonists for metabolic disorders while avoid toxicities caused by off-target and on-target mechanisms.

From Functional Fatty Acids to Potent and Selective Natural-Product-Inspired Mimetics via Conformational Profiling

“…These studies have resulted in the identification of leads for the development of potentially valuable agonists of GPR40 31 that reside within the same arbitrary class of mimetics prepared (Class I) but contain different stereochemical features. For example, the less potent GPR40 agonist congeners 1-C and 1-F are enantiomers of one another, while the more potent mimetic (1-E) is a unique enantiodefined diastereomer of these other ligands.…”

Advances in Research on Type 2 Diabetes Mellitus Targets and Therapeutic Agents

“…GPR40 belongs to the class A GPCRs, a member of the rhodopsin-like family with a conventional seven transmembrane structural domain and an additional eight helices at the C-terminus linked to palmitoylated cysteines, which can be activated using endogenous medium-and long-chain fatty acids and their derivatives [31,32]. It is mainly distributed in pancreatic β-cells, intestinal endocrine L, K, and I cells, pancreatic α-cells, and the central nervous system [33,34]. GPR40 has two binding sites, an endogenous FFA-binding orthosteric site and a variant binding site (interhelical A1 site and extrahelical A2 site) [33], which can initiate different regulatory mechanisms (Figure 2).…”

“…GPR40 has two binding sites, an endogenous FFA-binding orthosteric site and a variant binding site (interhelical A1 site and extrahelical A2 site) [33], which can initiate different regulatory mechanisms (Figure 2). The orthosteric site and the A1 site are coupled as Gαq/11, and, when activated, increases intracellular Ca 2+ levels, causing glucose-dependent insulin secretion (GSIS) [31,33,34]. The A2 site is a lipid-rich region that, when bound, stabilizes a conformation important for Gαs coupling, which increases intracellular cAMP levels, causing the secretion of enterostatin [31,34].…”

“…The orthosteric site and the A1 site are coupled as Gαq/11, and, when activated, increases intracellular Ca 2+ levels, causing glucose-dependent insulin secretion (GSIS) [31,33,34]. The A2 site is a lipid-rich region that, when bound, stabilizes a conformation important for Gαs coupling, which increases intracellular cAMP levels, causing the secretion of enterostatin [31,34]. GPR40 also activates the β-arrestin-mediated signaling pathway, which is associated with GSIS [33].…”

“…GPR40 also activates the β-arrestin-mediated signaling pathway, which is associated with GSIS [33]. The GPR40 agonists currently developed are divided into partial agonists and full agonists/orthoallosteric modulation (AgoPAM) agonists, with partial agonists generally activating only Gαq/11 and full agonists activating both Gαq/11 and Gαs; however, neither are available for clinical use due to either their poor efficacy or severe side effects [34]. TAK-875, the only GPR40 agonist that has entered phase III clinical trials [35], is a partial agonist bound to the A1 site and significantly reduces HbA1c levels in patients with T2DM [33,34].…”