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Crystal Structure of Human WRN helicase with compound 4
Structural highlights
DiseaseWRN_HUMAN Defects in WRN are a cause of Werner syndrome (WRN) [MIM:277700. WRN is a rare autosomal recessive progeroid syndrome characterized by the premature onset of multiple age-related disorders, including atherosclerosis, cancer, non-insulin-dependent diabetes mellitus, ocular cataracts and osteoporosis. The major cause of death, at a median age of 47, is myocardial infarction. Currently all known WS mutations produces prematurely terminated proteins.[1] Defects in WRN may be a cause of colorectal cancer (CRC) [MIM:114500. FunctionWRN_HUMAN Multifunctional enzyme that has both magnesium and ATP-dependent DNA-helicase activity and 3'->5' exonuclease activity towards double-stranded DNA with a 5'-overhang. Has no nuclease activity towards single-stranded DNA or blunt-ended double-stranded DNA. Binds preferentially to DNA substrates containing alternate secondary structures, such as replication forks and Holliday junctions. May play an important role in the dissociation of joint DNA molecules that can arise as products of homologous recombination, at stalled replication forks or during DNA repair. Alleviates stalling of DNA polymerases at the site of DNA lesions. Important for genomic integrity. Plays a role in the formation of DNA replication focal centers; stably associates with foci elements generating binding sites for RP-A (By similarity).[2] [3] [4] [5] [6] Publication Abstract from PubMedWerner 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 1 via an extensive screening and hit triage. Co-crystal structure of 1 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 4 as a covalent WRN functional inhibitor with improved stability. Further optimization led to potent compound 26 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 26 was achieved. Design of Cyclic Vinyl Sulfones as WRN Covalent Inhibitors from Noncovalent Binders.,Caravella JA, Toms AV, Sitnikov N, Bartels F, Svensson R, O'Hagan SJ, Borthwick JA, Campos S, Yin Y, Zhao X, Li L, Liu R, Talbot E, Kong H, Adolf Freund RR, Browning B, Genung NE, Carreiro S, Brennan D, Graves AP, Loh C, Tummino P, Edmondson SD, Li D J Med Chem. 2026 Apr 29. doi: 10.1021/acs.jmedchem.6c00328. PMID:42054607[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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