2848-LB: OBT-676, a Novel Oral Small Molecule Combining DACRA Full Agonism with “Triple-G” Partial Agonism for the Treatment of Metabolic Diseases

Introduction and Objective: Clinical evidence suggests that integrating Dual Amylin and Calcitonin Receptor Agonism (DACRA) with incretin and glucagon receptor signaling may provide a synergistic mechanism for appetite suppression, weight loss, and improved insulin sensitivity. By targeting a discrete binding pocket shared across major metabolic receptors, we have engineered small-molecule agonists that achieve high-potency, full-efficacy DACRA agonism together with partial agonism of the GLP-1, GIP, and glucagon receptors. Methods: Cryo-EM structural data were used to identify prospective amino acid contact sites, enabling in silico docking analysis of potential small molecule agonists. Identified molecules were functionally screened for agonism (cAMP stimulation) at human AMY-1, AMY-3, calcitonin, GLP-1, GIP, and glucagon receptors stably expressed in CHO-K1 cells. OBT-676 was evaluated for its acute effect on food intake in a diet-induced obesity (DIO) rat model. Results: OBT-676 exhibited full agonism at AMY-1, AMY-3, and calcitonin receptors with picomolar potency (<150 pM), and partial agonism (40-65%) at the GLP-1, GIP, and glucagon receptors with nanomolar potency (<15 nM). Oral administration of OBT-676 significantly reduced acute food intake in DIO rats. Conclusion: OBT-676 represents a novel class of orally bioavailable small molecule DACRA/Triple-G agonists that uniquely combine amylin receptor full agonism with partial agonism at the GLP-1, GIP, and glucagon receptors. This DACRA-GGG small molecule class represents a potential therapeutic alternative to injectable peptide combination products for metabolic disease therapy. Disclosure W. Wen: None. P. Beckett: None. M. Lewis: Other - Board Member, Employee, and Shareholder; Current; Oban BioPharma, Inc. D. Chalmers: None. Funding Oban BioPharma Inc.