Insilico nominates VAV1 degrader for autoimmune diseases

Insilico Medicine has nominated ISM9546, an orally bioavailable, peripheral-restricted VAV1 molecular glue degrader, as a preclinical candidate for autoimmune diseases including IBD and RA. VAV1 is involved in immune cell signaling, activation, proliferation, cytoskeletal dynamics and cytokine secretion, but has been considered difficult to drug because it lacks a classic small-molecule binding pocket.

The candidate was developed using Insilico’s Pharma.AI platform and Chemistry42 generative chemistry system. Chemistry42 integrates more than 40 generative models and predictive modules to support molecular generation, property prediction and multi-parameter optimization, with the team using design-make-test-analyze iterations to balance potency with reduced CNS exposure.

In preclinical studies, ISM9546 showed sub-nanomolar VAV1 degradation potency across cell-based assays and consistent efficacy in inflammatory bowel disease animal models. Histopathology scores improved by approximately 60%, while 14-day rodent and non-human primate toxicity evaluations indicated favorable tolerability and broad safety margins. ISM9546 is Insilico’s 35th preclinical candidate since 2021 and its 11th PCC within the first 10 months of 2026.