6DJC

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

Summary for 6DJC

• Entry DOI: 10.2210/pdb6djc/pdb
• Descriptor: 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)
• Functional Keywords: transcription, inhibitor, histone acetylation, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 32808.81

Authors

Ren, C.,Zhou, M.M. (deposition date: 2018-05-25, release date: 2018-07-25, Last modification date: 2023-10-11)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.46 Å)