AI-assisted delivery of novel covalent WRN inhibitors from a non-covalent fragment screen

  • Bioorg Med Chem Lett. 2025 Sep 30:131:130421. doi: 10.1016/j.bmcl.2025.130421.
Geoffrey M T Smith  1 ,  Laksh Aithani  2 ,  Charlotte E Barrett  2 ,  Alwin O Bucher  2 ,  Christopher D O Cooper  2 ,  Sébastien L Degorce  2 ,  Andrew S Doré  2 ,  Catherine T Fletcher  2 ,  Sophie Huber  2 ,  Rosemary Huckvale  2 ,  Amanda J Kennedy  2 ,  Abigail A Mornement  2 ,  Mark Pickworth  2 ,  Prakash Rucktooa  2 ,  Conor C G Scully  2 ,  Sarah E Skerratt  2
Affiliations
  • 1. CHARM Therapeutics Ltd., B900, Babraham Research Campus, Babraham, Cambridge, CB22 3AT, UK.. Electronic address: [email protected].
  • 2. CHARM Therapeutics Ltd., B900, Babraham Research Campus, Babraham, Cambridge, CB22 3AT, UK.
PMID: 41038585 DOI: 10.1016/j.bmcl.2025.130421
Abstract

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.

Keywords
BLM; Covalent; Fragment screen; Helicase; Inhibitor; Protein ligand co-folding; SBDD; Structure-activity relationship (SAR); WRN; Werner.
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