Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers.

ABSTRACT: The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens^1-6. Despite advances in treatment with immune checkpoint inhibitors^7-10, there is an unmet need in the treatment of MSI cancers^11-14. Here we report the structural, biochemical, cellular and pharmacological characterization of the clinical-stage WRN helicase inhibitor HRO761, which was identified through an innovative hit-finding and lead-optimization strategy. HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation. Pharmacological inhibition by HRO761 recapitulated the phenotype observed by WRN

SUBMITTER: Ferretti S 

PROVIDER: S-EPMC11078746 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature