ISM9546

ISM9546 is an orally bioavailable, peripherally restricted molecular glue degrader designed to target Vav guanine nucleotide exchange factor 1 (VAV1) for the treatment of autoimmune diseases, including inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). Developed by Insilico Medicine using its proprietary Pharma.AI platform, ISM9546 induces the degradation of VAV1, a key signaling node in immune cell activation that has historically been considered 'undruggable' due to the absence of a classic small-molecule binding pocket. In preclinical studies, ISM9546 demonstrated sub-nanomolar VAV1 degradation potency across multiple cell-based assays and robust efficacy in animal models of IBD, significantly reducing Disease Activity Index scores and cutting histopathological pathology scores by approximately 60%. Its peripheral restriction profile is designed to minimize central nervous system (CNS) exposure and associated risks.