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Spatially constrained tandem bromodomain inhibition bolsters sustained repression of BRD4 transcriptional activity for TNBC cell growth.


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.

SUBMITTER: Ren C 

PROVIDER: S-EPMC6077712 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Spatially constrained tandem bromodomain inhibition bolsters sustained repression of BRD4 transcriptional activity for TNBC cell growth.

Ren Chunyan C   Zhang Guangtao G   Han Fangbin F   Fu Shibo S   Cao Yingdi Y   Zhang Fan F   Zhang Qiang Q   Meslamani Jamel J   Xu Yaoyao Y   Ji Donglei D   Cao Lingling L   Zhou Qian Q   Cheung Ka-Lung KL   Sharma Rajal R   Babault Nicolas N   Yi Zhengzi Z   Zhang Weijia W   Walsh Martin J MJ   Zeng Lei L   Zhou Ming-Ming MM  

Proceedings of the National Academy of Sciences of the United States of America 20180716 31


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 const  ...[more]

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