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Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers

Nature. 2024-04; 
Stephane Ferretti, Jacques Hamon, Ruben de Kanter, Clemens Scheufler,Henrik M?bitz, Marta Cortés-Cros
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CRISPR RNAs/Cas9 Proteins(INACTIVE) HCTT116 cells with a knock-in of alanine instead of cysteine at position 727 of the WRN protein were generated using standard CRISPR techniques and the following sgRNA sequence for cutting AATCTCAGATCACCTGTAC, and the following ssDNA sequence as a donor GGAAAATCGTTCTAAATCTAATCTCAAAACACAAAAACAAATTCGAAA, both from GenScript. Get A Quote

摘要

The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens1-6. Despite advances in treatment with immune checkpoint inhibitors7-10, there is an unmet need in the treatment of MSI cancers11-14. 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 HRO... More

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