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J Med Chem. 2017 Jun 8;60(11):4533-4558. doi: 10.1021/acs.jmedchem.6b01761. Epub 2017 Mar 2.

Drug Discovery Targeting Bromodomain-Containing Protein 4.

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Chemical Biology Program, Department of Pharmacology and Toxicology, ‡Department of Internal Medicine, §Sealy Center for Molecular Medicine, ξInstitute for Translational Sciences, University of Texas Medical Branch , Galveston, Texas 77555, United States.


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.

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