Spatially constrained tandem bromodomain inhibition bolsters sustained repression of BRD4 transcriptional activity for TNBC cell growth.
Chunyan RenGuangtao ZhangFangbin HanShibo FuYingdi CaoFan ZhangQiang ZhangJamel MeslamaniYaoyao XuDonglei JiLingling CaoQian ZhouKa-Lung CheungRajal SharmaNicolas BabaultZhengzi YiWeijia ZhangMartin J WalshLei ZengMing-Ming ZhouPublished in: Proceedings of the National Academy of Sciences of the United States of America (2018)
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.
Keyphrases
- transcription factor
- cell cycle
- dna damage
- induced apoptosis
- mass spectrometry
- multiple sclerosis
- ms ms
- cell proliferation
- bone marrow
- cell cycle arrest
- signaling pathway
- young adults
- dna methylation
- endoplasmic reticulum stress
- binding protein
- heat shock
- small molecule
- heat stress
- amino acid
- protein protein
- pi k akt
- genome wide analysis
- childhood cancer