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

Authors

Chong Huang, Jingxin Qiao, Mengqiu Zhou, Xin Yang, Lengjing Zhu, Jinxiao Ru, Le Du, Wuxin Liu, Yan Chen, Anjie Xia, Linli Li, Shengyong Yang

Published in

Angewandte Chemie (International ed. in English). Pages e6947632. Oct 12, 2026. Epub Oct 12, 2026.

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.

PMID:
42865071
Bibliographic data and abstract were imported from PubMed on 13 Oct 2026.

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