Drug Discovery Targeting Bromodomain-Containing Protein 4
Open Access
- 2 March 2017
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 60 (11), 4533-4558
- https://doi.org/10.1021/acs.jmedchem.6b01761
Abstract
BRD4, the most extensively studied member of the BET family, is an epigenetic regulator that localizes to DNA via binding to acetylated histones and controls the expression of therapeutically important gene regulatory networks through the recruitment of transcription factors to form mediator complexes, phosphorylating RNA polymerase II, and by its intrinsic histone acetyltransferase activity. Disrupting the protein–protein interactions between BRD4 and acetyl-lysine has been shown to effectively block cell proliferation in cancer, cytokine production in acute inflammation, and so forth. To date, significant efforts have been devoted to the development of BRD4 inhibitors, and consequently, a dozen have progressed to human clinical trials. Herein, we summarize the advances in drug discovery and development of BRD4 inhibitors by focusing on their chemotypes, in vitro and in vivo activity, selectivity, relevant mechanisms of action, and therapeutic potential. Opportunities and challenges to achieve selective and efficacious BRD4 inhibitors as a viable therapeutic strategy for human diseases are also highlighted.Keywords
Funding Information
- Welch Foundation
- Sanofi
- U.S. Department of Defense (BC160038)
- Cancer Prevention and Research Institute of Texas
- National Institute on Drug Abuse (P30 DA028821, R01 DA038446)
- Institute for Translational Sciences, University of Texas Medical Branch
- Center for Addiction Research, University of Texas Medical Branch at Galveston
- Sealy and Smith Foundation
- Sealy Center for Molecular Medicine, University of Texas Medical Branch at Galveston
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