VVD-133214

VVD-133214 (RO7589831, VVD214) is an orally active, allosteric WRN inhibitor that covalently targets helicase domain Cys727 (hWRN(519-1227) DNA unwinding IC50 = 130 nM with and 1.3 μM without ATP preincubation). VVD214 binds WRN in a nucleotide-cooperative manner, causing widespread double-stranded DNA breaks, nuclear swelling and cell death in cells with high microsatellite instability (MSI-high, MSI-H; HCT-116 GI50 = 66 nM), but not in microsatellite-stable (MSS) cells (SW480 GI50 > 20 μM). VVD214 causes tumour regression in multiple MSI-H colorectal cancer cell lines-derived and patient-derived xenograft models in vivo (20 mg/kg via daily p.o.).