VVD-133214

VVD-133214 is a clinical-stage covalent allosteric inhibitor of Werner helicase (WRN), developed for the treatment of cancers with high microsatellite instability (MSI-H). It selectively binds to cysteine 727 in the WRN helicase domain and locks the enzyme in a rigid conformation that abrogates its function. This inhibition leads to double-stranded DNA breaks, nuclear swelling, and cell death specifically in MSI-H tumor cells but not in microsatellite-stable cells. The compound has demonstrated robust antitumor activity and tumor regression in preclinical models of MSI-H colorectal cancer and patient-derived xenografts. Its mechanism circumvents competition from endogenous ATP by targeting an allosteric pocket rather than the ATP-binding site. The drug is currently being evaluated in a Phase 1 clinical trial sponsored by Roche[1][2][4][5][8].

Other names

RG6457RG-6457RG 6457