Discovery of a Potent and Selective First-In-Class Antagonist of GPR15 With In Vivo Anti-Obesity Activity.

Abstract

GPR15 (G Protein-coupled Receptor 15), an atypical chemokine receptor, is implicated in the pathogenesis of multiple diseases, yet small-molecule GPR15 antagonists remain undeveloped. Herein, we identify and characterize YL410, the first-in-class potent and selective GPR15 antagonist. In the cAMP-GloSensor assay, YL410 inhibits GPR15 with an IC50 of 0.027 ± 0.005 µM, and displays high selectivity against a panel of related GPCRs and kinases. It suppresses GPR15L-induced Jurkat T-cell migration, and exhibits favorable pharmacokinetics and acceptable safety. Molecular docking, replicated molecular dynamics simulations, quantitative contact analyses, and mutagenesis experiments support a plausible orthosteric binding model for YL410, maintained by a reproducible network of polar and hydrophobic contacts, which rationalizes its potent antagonism and observed structure-activity relationships (SAR). Complementary AI-based structure predictions (AlphaFold3, Chai-1, and Boltz) recapitulated the energetically accessible orthosteric poses but not the dynamically stable pose selected by the MD simulations, underscoring the importance of kinetic-stability validation in antagonist pose selection. Notably, in a diet-induced obesity (DIO) mouse model, YL410 administration induced significant weight loss and exerted blood glucose-lowering effects. Collectively, this study presents the first potent, selective, and in vivo efficacious GPR15 antagonist, providing new insights into the development of therapeutics for the treatment of obesity.