Compound 1

Compound 1 is a novel, potent, and highly selective small molecule negative allosteric modulator (NAM) of the G protein-coupled receptor 68 (GPR68), also known as ovarian cancer G-protein-coupled receptor 1 (OGR1). GPR68 is a pH-sensing G protein-coupled receptor (GPCR) that is activated under acidic conditions, which are characteristic of tumor microenvironments and inflammatory tissues. Developed through a strategic collaboration between BenevolentAI and AstraZeneca, Compound 1 inhibits signaling through both the Gs (cAMP) and Gq/11 (inositol phosphate) pathways. While primarily highlighted for its role in modulating the immunosuppressive phenotype of colorectal cancer-associated fibroblasts (CAFs) and reducing tumor growth in preclinical models, GPR68 was also identified by BenevolentAI's platform as a first-in-class target for obesity (DOID:9970). The compound is orally bioavailable and demonstrates the ability to reduce pro-inflammatory cytokine release (such as IL-6 and IL-11) and fibrotic markers. It is currently being explored for its therapeutic potential in metabolic diseases, oncology, and inflammatory conditions like ulcerative colitis.