About this poster
In this poster, we present IRBM’s multidisciplinary approach to developing covalent inhibitors targeting cysteine 727 of Werner helicase (WRN), a synthetic lethality target in mismatch repair-deficient (dMMR)/microsatellite instability (MSI-H) colorectal cancers. We describe the assay cascade established to identify and characterize novel covalent pharmacophores, leveraging biochemical, LC/MS, and cell-based assays. Our findings highlight two series of ATP-competitive inhibitors with limited cellular activity and ATP-cooperative inhibitors demonstrating robust biochemical and cellular potency. Ongoing optimization focuses on enhancing the biochemical and cellular profiles of these covalent WRN inhibitors.
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Discovery of new covalent Werner helicase inhibitors poster, code 25002