9RTI

Structure of WRN in complex with ATPgS and covalent ligand Compound 7

This is a non-PDB format compatible entry.

Summary for 9RTI

• Entry DOI: 10.2210/pdb9rti/pdb
• Descriptor: Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN, PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER, DIMETHYL SULFOXIDE, ... (10 entities in total)
• Functional Keywords: dna damage repair, inhibitor, complex, helicase, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 51558.38

Authors

Fletcher, C.T.,Rucktooa, P. (deposition date: 2025-07-02, release date: 2025-10-22, Last modification date: 2025-11-05)

Primary citation

Smith, G.M.T.,Aithani, L.,Barrett, C.E.,Bucher, A.O.,Cooper, C.D.O.,Degorce, S.L.,Dore, A.S.,Fletcher, C.T.,Huber, S.,Huckvale, R.,Kennedy, A.J.,Mornement, A.A.,Pickworth, M.,Rucktooa, P.,Scully, C.C.G.,Skerratt, S.E.
AI-assisted delivery of novel covalent WRN inhibitors from a non-covalent fragment screen.
Bioorg.Med.Chem.Lett., 131:130421-130421, 2025

PubMed 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.

PubMed: 41038585
DOI: 10.1016/j.bmcl.2025.130421

Experimental method

X-RAY DIFFRACTION (2.197 Å)