10AP

Crystal Structure of Human WRN helicase with compound 26

This is a non-PDB format compatible entry.

Summary for 10AP

• Entry DOI: 10.2210/pdb10ap/pdb
• Descriptor: Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN, (2R)-N-[(3R)-1,1-dioxo-1lambda~6~-thiolan-3-yl]-N-{[2-(2-hydroxypropan-2-yl)pyridin-4-yl]methyl}-2-methoxy-2-[(1M)-3,3',4'-trifluoro[1,1'-biphenyl]-4-yl]acetamide, ADENOSINE-5'-TRIPHOSPHATE, ... (6 entities in total)
• Functional Keywords: dna helicase recq family allosteric inhibitor, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 52333.90

Authors

Toms, A.V.,Caravella, J.A.,Sitnikov, N.,Bartels, F.,Svensson, R.,Jacques O'Hagan, S.,Borthwick, J.,Campos, S.,Yin, Y.,Zhao, X.,Li, L.,Talbot, E.,Kong, H.,Freund, R.R.A.,Browning, B.,Genung, N.E.,Carreiro, S.,Brennan, D.,Graves, A.P.,Loh, C.,Tummino, P.,Edmonson, S.D.,Li, D. (deposition date: 2026-01-08, release date: 2026-05-13)

Primary citation

Caravella, J.A.,Toms, A.V.,Sitnikov, N.,Bartels, F.,Svensson, R.,O'Hagan, S.J.,Borthwick, J.A.,Campos, S.,Yin, Y.,Zhao, X.,Li, L.,Liu, R.,Talbot, E.,Kong, H.,Adolf Freund, R.R.,Browning, B.,Genung, N.E.,Carreiro, S.,Brennan, D.,Graves, A.P.,Loh, C.,Tummino, P.,Edmondson, S.D.,Li, D.
Design of Cyclic Vinyl Sulfones as WRN Covalent Inhibitors from Noncovalent Binders.
J.Med.Chem., 2026

PubMed Abstract: Werner syndrome helicase (WRN) is a DNA damage response protein selectively required for the survival of tumors with high microsatellite instability (MSI-H). We identified a noncovalent WRN inhibitor via an extensive screening and hit triage. Co-crystal structure of with the WRN helicase domain revealed a unique mechanism of inhibition via stabilization of inactive protein conformation and led to identification of cysteine 727 as a target for covalent inhibition. Structure-based drug design (SBDD) and a computational workflow resulted in the discovery of cyclic vinyl sulfone as a covalent WRN functional inhibitor with improved stability. Further optimization led to potent compound demonstrating exquisite selectivity to WRN in cell proteomic profiling and strong in vivo efficacy in an MSI-H Xenograft tumor model with no effect in microsatellite stable xenograft tumors. Therefore, a proof of concept of synthetic lethal MSI-H tumor cell growth inhibition by covalent inhibitor was achieved.

PubMed: 42054607
DOI: 10.1021/acs.jmedchem.6c00328

Experimental method

X-RAY DIFFRACTION (2.58 Å)