5Y8C

Crystal Structure Analysis of the BRD4

5Y8C の概要

• エントリーDOI: 10.2210/pdb5y8c/pdb
• 分子名称: Bromodomain-containing protein 4, NITRATE ION, 5-chloranyl-2-methoxy-N-(6-methoxy-3-methyl-1,2-benzoxazol-5-yl)benzenesulfonamide, ... (6 entities in total)
• 機能のキーワード: brd4(1), bromodomain, transcription
• 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: 17232.16

構造登録者

Xu, Y.,Zhang, Y.,Song, M.,Wang, C. (登録日: 2017-08-21, 公開日: 2018-06-13, 最終更新日: 2023-11-22)

主引用文献

Zhang, M.,Zhang, Y.,Song, M.,Xue, X.,Wang, J.,Wang, C.,Zhang, C.,Li, C.,Xiang, Q.,Zou, L.,Wu, X.,Wu, C.,Dong, B.,Xue, W.,Zhou, Y.,Chen, H.,Wu, D.,Ding, K.,Xu, Y.
Structure-Based Discovery and Optimization of Benzo[ d]isoxazole Derivatives as Potent and Selective BET Inhibitors for Potential Treatment of Castration-Resistant Prostate Cancer (CRPC)
J. Med. Chem., 61:3037-3058, 2018

PubMed Abstract: The bromodomain and extra-terminal (BET) family proteins have gained increasing interest as drug targets for treatment of castration-resistant prostate cancer (CRPC). Here, we describe the design, optimization, and evaluation of benzo[ d]isoxazole-containing compounds as potent BET bromodomain inhibitors. Cocrystal structures of the representative inhibitors in complex with BRD4(1) provided solid structural basis for compound optimization. The two most potent compounds, 6i (Y06036) and 7m (Y06137), bound to the BRD4(1) bromodomain with K values of 82 and 81 nM, respectively. They also exhibited high selectivity over other non-BET subfamily members. The compounds potently inhibited cell growth, colony formation, and the expression of AR, AR regulated genes, and MYC in prostate cancer cell lines. Compounds 6i and 7m also demonstrated therapeutic effects in a C4-2B CRPC xenograft tumor model in mice. These potent and selective BET inhibitors represent a new class of compounds for the development of potential therapeutics against CRPC.

PubMed: 29566488
DOI: 10.1021/acs.jmedchem.8b00103

実験手法

X-RAY DIFFRACTION (1.42 Å)