1139-P: Discovery of a Potent, Orally Efficacious Small Molecule Agonist of Glucagon-Like Peptide-1 (GLP-1) Receptor

Introduction: Given its physiological roles, GLP-1 agonists are considered a class of drugs used in the treatment of type 2 diabetes and obesity. These agents mimic 7-36 amide Semaglutide, increase insulin release, decrease glucagon secretion, and a slowing of gastric emptying but are injectables, week half-life, and cold chain storage limit their utility. Several small molecule agonists of the GLP-1 receptor have been investigated as potential alternatives to peptide-based GLP-1 agonists like Danuglipron, and Orforglipron. Here we present the discovery of the MLX-7005 series exhibited on target-specific GLP-1 agonist activity in its binding and cellular studies.

Methods: Tag-Lite GLP-1 receptor binding assay. Ca²⁺ mobilization in Min6-c4 cells. cAMP in PSC-HEK293 Cell Line Expressing GLP-1R. cAMP β-Cell Line 1.2B4. The cAMP Gs dynamic and a LANCE Ultra cAMP kit. GLP-1 agonist in db/db and DIO models of T2D and obesity.

Results: Small molecule GLP-1 agonists we discovered are orally available, stable, lower manufacturing costs than peptide-based drugs. We disclose MLX-7005 and its analogs, exhibiting potent activity in vitro MIN6 Ca2+ assay dose-dependently with an EC₅₀ of 241 nM and reference Danuglipron, GLP-1 peptide are 219 nM and 70 nM. MLX-7005 additional in vitro and in vivo pharmacology profile results consistent with its on-target potency. MLX-7005 has a high binding affinity to human GLP-1R. MLX-7005 strongly activated the GLP-1R cAMP pathway without inducing measurable β-arrestin recruitment signaling. The insulin secretion effect of MLX-7005 was evaluated in a functional human pancreatic beta cell line, in which MLX-7005 showed dose-dependent induction of insulin secretion.

Conclusion: In conclusion, MLX-7005 is a highly potent, orally available, GLP-1 agonist. pre-clinical in vivo DIO, db/db rodent models studies are underway along with safety, and tolerability to further evaluation as a potential therapy for T2DM and obesity will be presented.