SUN-580 A Phase III Small Molecule GLP1R Agonist Acts As a Pharmacological Chaperone for Misfolded GLP1R Mutants

Abstract Disclosure: Y. Tao: None. S. Lian: None. F. Gbahou: None. J. Dam: None. R. Jockers: None. Glucagon-like peptide 1 (GLP1) is an incretin hormone released in response to food intake and increase in blood glucose. GLP1 regulates glucose homeostasis via its membrane receptor, GLP1R, a member of G protein-coupled receptor (GPCR) superfamily. GLP1R typically activates the cAMP signaling pathway to promote insulin secretion. We recently showed that many naturally occurring variants in GLP1R that are associated with increased adiposity and impaired glucose balance have decreased cell surface expression (Gao W. et al., 2023. Nature Metabolism 5:1673-1684). Pharmacological chaperone (pharmacoperone) are small molecule lipophilic ligands that can bind to the misfolded mutants retained intracellularly and facilitate the folding and anterograde trafficking of the mutants. Pharmacoperones have been identified for mutant GPCRs associated with several diseases, including endocrine diseases such as nephrogenic diabetes insipidus, obesity, and hypogonadism. In this study, we identified a small molecule GLP1R agonist, in Class III clinical trials, as a potent pharmacoperone. In HEK293 cells, cell surface expression was increased in most of the 21 mutants tested, and some mutants increased up to 20-fold, reaching that of the wild-type (WT) GLP1R. Indeed, the cell surface expression of the WT GLP1R was also increased, suggesting that the folding of the WT GLP1R was not optimal and could be enhanced. Total expression of these receptors was not affected. We further showed that a 24h, but not an acute, treatment with the small molecule GLP1R agonist increased cAMP production of several mutants. Some of them also became responsive to additional GLP1(7-36) stimulation. We then expressed the mutant receptors in INS-1 insulinoma cells lacking endogenous GLP1R. A 24h treatment with the small molecule GLP1R agonist restored GLP1(7-36)-induced insulin secretion in these cells for at least five GLP1R mutants. In summary, we identified a small molecule GLP1R agonist as a pharmacoperone rescuing impaired insulin secretion of natural GLP1R mutants. This can become a potential precision medicine strategy for treatment patients with T2DM due to GLP1R mutations. Presentation: Sunday, July 13, 2025