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

Proceedings of the National Academy of Sciences of the United States of America
Chunyan RenMing-Ming Zhou

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.

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Citations

Oct 5, 2019·Nature Structural & Molecular Biology·Nilesh Zaware, Ming-Ming Zhou
Jul 6, 2019·Nature Reviews. Drug Discovery·Andrea G CochranRobert J Sims
Mar 24, 2020·Nature Structural & Molecular Biology·Xinye HanLei Zeng
Jun 11, 2020·Molecular Biology of the Cell·Hengyi ShaoKunxin Luo
Jul 25, 2020·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Jessica Y HsuRushita A Bagchi
Jan 21, 2021·Cellular Oncology (Dordrecht)·Angeliki AndrikopoulouFlora Zagouri
Mar 16, 2021·Frontiers in Immunology·Adam P CribbsUdo Oppermann
Sep 17, 2020·European Journal of Medicinal Chemistry·Rajibul Islam, Kok Wai Lam
Apr 15, 2021·Current Opinion in Chemical Biology·Isabelle A EngelbergStephen V Frye
May 27, 2021·The Journal of Experimental Medicine·J Justin MilnerAnanda W Goldrath

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