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

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

  • Proc Natl Acad Sci U S A. 2018 Jul 31;115(31):7949-7954. doi: 10.1073/pnas.1720000115.
Chunyan Ren 1 Guangtao Zhang 1 2 Fangbin Han 2 Shibo Fu 2 Yingdi Cao 2 Fan Zhang 1 Qiang Zhang 1 2 Jamel Meslamani 1 Yaoyao Xu 2 Donglei Ji 2 Lingling Cao 2 Qian Zhou 2 Ka-Lung Cheung 1 2 Rajal Sharma 1 Nicolas Babault 1 Zhengzi Yi 3 Weijia Zhang 3 Martin J Walsh 1 Lei Zeng 1 2 Ming-Ming Zhou 4
Affiliations

Affiliations

  • 1 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
  • 2 Bethune Institute of Epigenetic Medicine, The First Hospital, Jilin University, 130061 Changchun, China.
  • 3 Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
  • 4 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029; [email protected].
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.

Keywords

BRD4; TNBC; bivalent BET inhibitors; drug discovery; gene transcription.

Figures
Products