Challenges for the Discovery of Non-Covalent WRN Helicase Inhibitors.

Autor: Heuser A; Novartis Biomedical Research, Novartis Campus, CH-4056, Basel, Switzerland., Abdul Rahman W; Novartis Biomedical Research, Novartis Campus, CH-4056, Basel, Switzerland., Bechter E; Novartis Biomedical Research, Novartis Campus, CH-4056, Basel, Switzerland., Blank J; Novartis Biomedical Research, Novartis Campus, CH-4056, Basel, Switzerland., Buhr S; Novartis Biomedical Research, Novartis Campus, CH-4056, Basel, Switzerland., Erdmann D; Novartis Biomedical Research, Novartis Campus, CH-4056, Basel, Switzerland., Fontana P; Novartis Biomedical Research, Novartis Campus, CH-4056, Basel, Switzerland., Mermet-Meillon F; Novartis Biomedical Research, Novartis Campus, CH-4056, Basel, Switzerland., Meyerhofer M; Novartis Biomedical Research, Novartis Campus, CH-4056, Basel, Switzerland., Strang R; Novartis Biomedical Research, Novartis Campus, CH-4056, Basel, Switzerland., Schrapp M; Novartis Biomedical Research, Novartis Campus, CH-4056, Basel, Switzerland., Zimmermann C; Novartis Biomedical Research, Novartis Campus, CH-4056, Basel, Switzerland., Cortes-Cros M; Novartis Biomedical Research, Novartis Campus, CH-4056, Basel, Switzerland., Möbitz H; Novartis Biomedical Research, Novartis Campus, CH-4056, Basel, Switzerland., Hamon J; Novartis Biomedical Research, Novartis Campus, CH-4056, Basel, Switzerland.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2024 Apr 16; Vol. 19 (8), pp. e202300613. Date of Electronic Publication: 2024 Mar 07.
DOI: 10.1002/cmdc.202300613
Abstrakt: The 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.
(© 2024 Wiley‐VCH GmbH.)
Databáze: MEDLINE
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