About this poster
Werner helicase (WRN) has emerged as a compelling synthetic lethal target in microsatellite instability-high (MSI-H) cancers, yet its dynamic helicase domain presents significant challenges for traditional drug discovery. This poster presents IRBM’s electrophile-first drug discovery platform — a covalent fragment library of over 1,600 compounds paired with a multi-assay kinetic toolbox (enzymatic unwinding assays, intact mass LC-HRMS, peptide mapping, and covalent docking) — applied to rapidly identify ATP-competitive covalent inhibitors selectively engaging Cysteine 727 of WRN. Screening, hit expansion, and X-ray crystallography together confirmed the covalent binding mode and provided a structural rationale for further structure-based optimization. Download the poster to explore the full screening cascade, SAR findings, and crystallographic data in detail.
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WRN Covalent Fragment poster, code 26005