@article{e5addedf62584225b5d27d9d646b622f,
title = "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 proinflam-matory 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, Bivalent BET inhibitors, Drug discovery, Gene transcription, TNBC",
author = "Chunyan Ren and Guangtao Zhang and Fangbin Han and Shibo Fu and Yingdi Cao and Fan Zhang and Qiang Zhang and Jamel Meslamani and Yaoyao Xu and Donglei Ji and Lingling Cao and Qian Zhou and Cheung, {Ka lung} and Rajal Sharma and Nicolas Babault and Zhengzi Yi and Weijia Zhang and Walsh, {Martin J.} and Lei Zeng and Zhou, {Ming Ming}",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Drs. Vivian Stojanoff and Silvia Russi and the staff of 14-1 beamline at the Stanford Synchrotron Radiation Light Source for assisting with X-ray data collection and the staff of the Genomics Sequencing Core at the Icahn School of Medicine at Mount Sinai and the Epigenomics Core of Weill Cornell Medical College for generating RNA-seq data. We also thank Drs. Alaa Abdine, Rinku Jain, Zhenzhen Wang, and Iban Ubarretxena for technical help for the DLS experiment, X-ray crystal structure analysis, and mathematical analysis, and Dr. Nadejda Tsankova for providing glioblastoma cell line U87. This work was supported in part by the research fund from the First Hospital of Jilin University, Jilin Province Science and Technology Development Program Grant 20160101076JC (to S.F.), and research grants from the Breast Cancer Alliance, Department of Defense Breast Cancer Research Program Breakthrough Award W81XWH15-1-0043, and the National Institutes of Health (to M.-M.Z.). Funding Information: We thank Drs. Vivian Stojanoff and Silvia Russi and the staff of 14-1 beamline at the Stanford Synchrotron Radiation Light Source for assisting with X-ray data collection and the staff of the Genomics Sequencing Core at the Icahn School of Medicine at Mount Sinai and the Epigenomics Core of Weill Cornell Medical College for generating RNA-seq data. We also thank Drs. Alaa Abdine, Rinku Jain, Zhenzhen Wang, and Iban Ubarretxena for technical help for the DLS experiment, X-ray crystal structure analysis, and mathematical analysis, and Dr. Nadejda Tsankova for providing glioblastoma cell line U87. This work was supported in part by the research fund from the First Hospital of Jilin University, Jilin Province Science and Technology Development Program Grant 20160101076JC (to S.F.), and research grants from the Breast Cancer Alliance, Department of Defense Breast Cancer Research Program Breakthrough Award W81XWH15-1-0043, and the National Institutes of Health (to M.-M.Z.). Publisher Copyright: {\textcopyright} 2018 National Academy of Sciences. All rights reserved.",
year = "2018",
month = jul,
day = "31",
doi = "10.1073/pnas.1720000115",
language = "English",
volume = "115",
pages = "7949--7954",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "31",
}