8HE8

Human ADP-ribosyltransferase 2 (PARP2) catalytic domain bound to a quinazoline-2,4(1H,3H)-dione inhibitor

8HE8 の概要

• エントリーDOI: 10.2210/pdb8he8/pdb
• 分子名称: Poly [ADP-ribose] polymerase 2, GLYCEROL, 1-[[4-fluoranyl-3-(3-oxidanylidene-4-pentan-3-yl-piperazin-1-yl)carbonyl-phenyl]methyl]quinazoline-2,4-dione, ... (4 entities in total)
• 機能のキーワード: parp-2, dna adp-ribosyltransferase, inhibitor, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 121018.93

構造登録者

Wang, X.Y.,Xu, B.L.,Zhou, J. (登録日: 2022-11-07, 公開日: 2023-11-08, 最終更新日: 2026-03-11)

主引用文献

Zhou, J.,Du, T.,Wang, X.,Yao, H.,Deng, J.,Li, Y.,Chen, X.,Sheng, L.,Ji, M.,Xu, B.
Discovery of Quinazoline-2,4(1 H ,3 H )-dione Derivatives Containing a Piperizinone Moiety as Potent PARP-1/2 Inhibitors─Design, Synthesis, In Vivo Antitumor Activity, and X-ray Crystal Structure Analysis.
J.Med.Chem., 66:14095-14115, 2023

PubMed Abstract: PARP-1/2 inhibitors have become an important therapeutic strategy for the treatment of HR-deficient tumors. However, discovery of new inhibitors with an improved and distinct pharmacological file still need enormous explorations. Herein, a series of novel highly potent PARP-1/2 inhibitors bearing an -substituted piperazinone moiety were achieved. In particular, was identified as a distinct PARP inhibitor, showing remarkable enzymatic activity not only toward PARP-1 (IC = 0.94 nM) and PARP-2 (IC = 0.87 nM) but also toward PARP-7 (IC = 0.21 nM), as well as high selectivity over other PARP isoforms. Furthermore, was orally bioavailable and significantly repressed the tumor growth in both breast cancer and prostate cancer xenograft model. The crystal structures of within PARP-1 and PARP-2 together with the predicted binding mode within PARP-7 revealed its binding features and provided insightful information for further developing highly potent and selective PARP-1 and/or PARP-7 inhibitors.

PubMed: 37843892
DOI: 10.1021/acs.jmedchem.3c01152

実験手法

X-RAY DIFFRACTION (3.05 Å)