Summary for 9OG3
| Entry DOI | 10.2210/pdb9og3/pdb |
| Descriptor | Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN, (3R,4S)-N-[(2R)-3-cyclohexyl-1-(dimethylamino)-1-oxopropan-2-yl]-1-[(2-fluoro-4-methylphenyl)acetyl]-4-[3-(2-oxo-2,3-dihydro-1H-1,3-benzimidazol-1-yl)propanamido]piperidine-3-carboxamide, ZINC ION, ... (4 entities in total) |
| Functional Keywords | werner syndrome helicase, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 48962.01 |
| Authors | Pemberton, O.A.,Tong, Y.,Nocek, B.,Tang, H.Y.H. (deposition date: 2025-04-30, release date: 2025-06-18) |
| Primary citation | Tong, Y.,Baker, K.A.,Chapman, A.M.,Elsen, N.L.,Fowler, F.,George, M.D.,Gesmundo, N.J.,Hatton, H.,Hickey, M.,Hutchins, C.W.,Jeffries, C.L.,Kelly, A.,Korepanova, A.,Miller, I.R.,Nocek, B.,Panchal, S.C.,Pemberton, O.A.,Qiu, W.,Talaty, N.N.,Hin Tang, H.Y.,Towne, D.,Zhang, M.,Zhao, Y.,Gopalakrishnan, S.M.,Sun, C.,Kort, M.E.,Dart, M.J.,Firestone, A.J. Validation, Key Pharmacophores, and X-ray Cocrystal Structures of Novel Biochemically and Cellularly Active WRN Inhibitors Derived from a DNA-Encoded Library Screen. J.Med.Chem., 2025 Cited by PubMed Abstract: A novel class of selective and potent WRN helicase antagonists identified via a DNA-encoded library screen was rigorously validated by various biophysical assays including ASMS, TSA, and SPR. Preliminary structure-activity-relationship studies identified the key pharmacophores and advanced the biochemical potency to single digit nanomolar. Potent analogs demonstrated anti-proliferative activities specifically in cell lines with a WRN genetic dependency. A crystal structure of a ligand-WRN complex revealed an unexpected large shift of the helicase domain compared to the apo WRN structure with ADP. These structural insights led to the successful design of covalent inhibitors and the identification of compound resistant WRN mutants that confirmed on-mechanism cellular activity. The covalent interaction between the ligand and at WRN Cys727 was confirmed by intact mass spectrometry and a bound crystal structure. The discovery of these unique WRN inhibitors provides more insight into the field and offers an opportunity to further optimize such molecules. PubMed: 40472162DOI: 10.1021/acs.jmedchem.4c03029 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.06 Å) |
Structure validation
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