Identification of VVD-214/RO7589831, a Clinical-Stage, Covalent Allosteric Inhibitor of WRN Helicase for the Treatment of MSI-High Cancers

Werner syndrome helicase (WRN) has emerged as a compelling
therapeutic
target for microsatellite instability-high (MSI-H) cancers, owing
to its selective dependency on the helicase activity of WRN. Despite
the inherent challenges in targeting helicases, our chemoproteomics
approach enabled the identification of compounds that covalently engage
C727 within an allosteric pocket of WRN, thereby inhibiting its ability
to unwind DNA. Through optimization of each molecular component, particularly
focusing on the vinyl sulfone warhead and C2 substitution at the pyrimidine
core, an optimal balance of intrinsic reactivity, inhibitory potency,
and metabolic stability was achieved, culminating in the identification
of VVD-214/RO7589831. This process underscored the tunability of the
vinyl sulfone warhead and its effectiveness in covalent drug discovery.
VVD-214 induced tumor regression in MSI-H colorectal cancer models
and is being evaluated as a promising therapeutic candidate for MSI-H
cancers.