Geoffrey M.T. Smith, Laksh Aithani, Charlotte E. Barrett, Alwin O. Bucher, Christopher D.O. Cooper, Sébastien L. Degorce, Andrew S. Doré, Catherine T. Fletcher, Sophie Huber, Rosemary Huckvale, Amanda J. Kennedy, Abigail A. Mornement, Mark Pickworth, Prakash Rucktooa, Conor C.G. Scully, Sarah E. Skerratt
Bioorganic & Medicinal Chemistry Letters, 2025
https://doi.org/10.1016/j.bmcl.2025.130421
Werner (WRN) helicase, has emerged as a promising therapeutic target for cancers associated with microsatellite instability (MSI). This letter describes the discovery of small molecule inhibitors from a fragment screen that occupy a cryptic, allosteric site of WRN helicase. Key findings include the identification of benzimidazole and amino-indazole scaffolds, exploiting their proximity to Cys727 via covalent modification. The use of our proprietary co-folding model DragonFold assisted the identification of novel WRN helicase inhibitors. These, together with near-neighbor profiling, offer tools for furthering the understanding of WRN and BLM helicase function, and potential therapeutic avenues for MSI-associated cancers.
