6DJC

Crystal structure of human Bromodomain-containing protein 4 (BRD4) bromodomain with MS645

6DJC の概要

• エントリーDOI: 10.2210/pdb6djc/pdb
• 分子名称: Bromodomain-containing protein 4, N,N'-(decane-1,10-diyl)bis{2-[(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetamide}, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: transcription, inhibitor, histone acetylation, transcription-inhibitor complex, transcription/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 32808.81

構造登録者

Ren, C.,Zhou, M.M. (登録日: 2018-05-25, 公開日: 2018-07-25, 最終更新日: 2023-10-11)

主引用文献

Ren, C.,Zhang, G.,Han, F.,Fu, S.,Cao, Y.,Zhang, F.,Zhang, Q.,Meslamani, J.,Xu, Y.,Ji, D.,Cao, L.,Zhou, Q.,Cheung, K.L.,Sharma, R.,Babault, N.,Yi, Z.,Zhang, W.,Walsh, M.J.,Zeng, L.,Zhou, M.M.
Spatially constrained tandem bromodomain inhibition bolsters sustained repression of BRD4 transcriptional activity for TNBC cell growth.
Proc. Natl. Acad. Sci. U.S.A., 115:7949-7954, 2018

PubMed Abstract: The importance of BET protein BRD4 in gene transcription is well recognized through the study of chemical modulation of its characteristic tandem bromodomain (BrD) binding to lysine-acetylated histones and transcription factors. However, while monovalent inhibition of BRD4 by BET BrD inhibitors such as JQ1 blocks growth of hematopoietic cancers, it is much less effective generally in solid tumors. Here, we report a thienodiazepine-based bivalent BrD inhibitor, MS645, that affords spatially constrained tandem BrD inhibition and consequently sustained repression of BRD4 transcriptional activity in blocking proliferation of solid-tumor cells including a panel of triple-negative breast cancer (TNBC) cells. MS645 blocks BRD4 binding to transcription enhancer/mediator proteins MED1 and YY1 with potency superior to monovalent BET inhibitors, resulting in down-regulation of proinflammatory cytokines and genes for cell-cycle control and DNA damage repair that are largely unaffected by monovalent BrD inhibition. Our study suggests a therapeutic strategy to maximally control BRD4 activity for rapid growth of solid-tumor TNBC cells.

PubMed: 30012592
DOI: 10.1073/pnas.1720000115

実験手法

X-RAY DIFFRACTION (1.46 Å)