Discovery of Gut-Targeted GPR40 Agonist K-757 and GPR119 Agonist K-833, a Combination Treatment for Metabolic Disorders PMID: 40708100

ADC Targets in Oncology

2026-04-10

Discovery of Gut-Targeted GPR40 Agonist K-757 and GPR119 Agonist K-833, a Combination Treatment for Metabolic Disorders

J Med Chem. 2025 Jul 24. doi: 10.1021/acs.jmedchem.5c01030.

Christopher R Moyes ¹ , Shuwen He ¹ , Simon Mathieu ¹ , Sara L Lehman ¹ , Macrina T Francisco ¹ , Eyal Vardy ¹ , Giuseppe Terracina ¹ , Ani Galstian ¹ , Monika J M Murphy ¹ , Gregory Poterewicz ¹ , Danny Kosinski ¹ , Xiaodong Yang ¹ , Shuqin Zheng ¹ , Bryan Chan ¹ , Matthew J Consolati ¹ , Richard Tschirret-Guth ¹ , Michael R Luzung ¹ , Robert Saklatvala ¹ , Gregory Rak ¹ , Robert Barretto ¹ , Jennifer Talaty ¹ , Annemarie Vance ¹ , Hong Zhang ¹ , Jiajun Liu ¹ , Ann E Weber ¹ , Brett Lauring ¹ , Shirly Pinto ¹ , Iyassu K Sebhat ¹

Affiliations

Abstract

Bariatric surgery provides long-term and robust weight loss in most patients. One leading hypothesis for this profound efficacy focuses on the increased activation of gut enteroendocrine cells (EECs), resulting in enhanced secretion of satiety Hormones. We describe herein an approach using a combination of gut-targeted small molecules to stimulate intestinal nutrient receptors and mirror some of the hormone effects of bariatric surgery. In preclinical studies, administration of GPR40 agonist K-757 in combination with GPR119 Agonist K-833 resulted in robust increases in the level of circulating Hormones. In initial clinical studies, pharmacokinetics and pharmacodynamics for each molecule were characterized and largely recapitulated the effects of the individual compounds in mice.