VVD-214

VVD-214 is a covalent inhibitor of the DNA helicase Werner syndrome protein (WRN).¹ It inhibits wild-type WRN (IC₅₀ = 0.13 µM) but not the mutant WRN^C727A. VVD-214 inhibits the growth of microsatellite instability-high (MSI-H) HCT116 colorectal cancer cells (GI₅₀ = 0.066 µM) but not microsatellite stable (MSS) SW480 colon adenocarcinoma cells or HCT116 cells expressing the WRN^C727A mutation (GI₅₀s = >20 µM for both). It induces DNA damage, apoptosis, and cell cycle arrest at the G₂ phase in HCT116 cells but not in SW480 cells. VVD-214 (10-20 mg/kg, p.o.) reduces tumor volume in multiple MSI-H colorectal cancer mouse xenograft models but not in MSS colorectal cancer mouse xenograft models.

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1. Baltgalvis, K.A., Lamb, K.N., Symons, K.T., et al. Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase. Nature 629(8011), 435-442 (2024).