Challenges for the Discovery of non-covalent WRN Helicase inhibitors

ChemMedChem. 2024 Feb 9:e202300613. doi: 10.1002/cmdc.202300613. Online ahead of print.ABSTRACTThe Werner Syndrome RecQ helicase (WRN) is a synthetic lethal target of interest for the treatment of cancers with microsatellite instability (MSI). Different hit finding approaches were initially tested. The identification of WRN inhibitors proved challenging due to a high propensity for artefacts via protein interference, i.e., hits inhibiting WRN enzymatic activities through multiple, unspecific mechanisms. Previously published WRN Helicase inhibitors (ML216, NSC19630 or NSC617145) were characterized in an extensive set of biochemical and biophysical assays and could be ruled out as specific WRN helicase probes. More innovative screening strategies need to be developed for successful drug discovery of non-covalent WRN helicase inhibitors.PMID:38334957 | DOI:10.1002/cmdc.202300613

Source: ChemMedChem - February 9, 2024 Category: Chemistry Authors: Alisa Heuser Wassim Abdul Rahman Elisabeth Bechter Jutta Blank Sylvia Buhr Dirk Erdmann Patrizia Fontana Fanny Mermet-Meillon Marco Meyerhofer Ross Strang Maxime Schrapp Catherine Zimmermann Marta Cortes-Cros Henrik M öbitz Jacques Hamon Source Type: research