9OG8

Crystal structure of WRN in complex with compound 43

これはPDB形式変換不可エントリーです。

9OG8 の概要

• エントリーDOI: 10.2210/pdb9og8/pdb
• 分子名称: Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN, (3R,4S)-N-[(2R)-3-cyclohexyl-1-(methylamino)-1-oxopropan-2-yl]-4-{3-[6-(ethanesulfonamido)-2-oxo-2,3-dihydro-1H-1,3-benzimidazol-1-yl]propanamido}-1-[(2-fluoro-4-methylphenyl)acetyl]piperidine-3-carboxamide, ZINC ION, ... (4 entities in total)
• 機能のキーワード: werner syndrome helicase, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 49055.12

構造登録者

Pemberton, O.A.,Tong, Y.,Nocek, B.,Tang, H.Y.H. (登録日: 2025-04-30, 公開日: 2025-06-18, 最終更新日: 2025-07-02)

主引用文献

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., 68:12434-12456, 2025

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: 40472162
DOI: 10.1021/acs.jmedchem.4c03029

実験手法

X-RAY DIFFRACTION (1.66 Å)