Abstract 4207: Discovery of WRN helicase inhibitors that covalently engage a novel, induced allosteric site

The RecQ helicase WRN is a synthetic lethal dependency in microsatellite instability-high (MSI-H) cancer and a therapeutic target of interest in that context. The two clinical-stage WRN inhibitors, HRO761 and RO7589831, both bind in an allosteric pocket near the interface of the two helicase domains (D1 and D2). To discover novel WRN inhibitors, we conducted a high-throughput phenotypic screen usi…