GPR40 Agonist Program

Our third preclinical program is a drug discovery program for the development of a liver safe GPR40 agonist, compared to other compounds in development, as a possible treatment for T2D.

GPR40, a G protein-coupled receptor for free fatty acids, also known as FFA1 or FFAR1, is a seven transmembrane GPCR highly expressed in pancreatic β-cells, intestinal L, K, and I cells and in neurons and responds to medium and long chain unsaturated fatty acids, resulting in increased insulin secretion only in the presence of elevated glucose levels. The receptor’s glucose dependency makes it an attractive target for developing potentially safe and effective therapies for type 2 diabetes. While the mechanism of action is not fully understood, previous published research suggests that GPR40 is mainly coupled with the G protein α-subunit of the Gq family (Gαq), which triggers an increase in phospholipase C (PLC) activity, leading to intracellular calcium mobilization and protein kinase C (PKC) activation. GPR40 is also expressed in enteroendocrine cells of the gastrointestinal tract, with activation resulting in the secretion of incretins such as GLP-1 and GIP, which can indirectly regulate insulin secretion.

We believe that identification of a GPR40 agonist that does not exhibit liver toxicity is achievable and discovery medicinal chemistry is ongoing. Our GPR40 agonist development program is currently at the discovery stage.