title: Drug Discovery Targeting Bromodomain-Containing Protein 4.
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.
authors.affiliation: 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.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Pingyuan
authors.initials: P
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Haiying
authors.initials: H
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Wold
authors.affiliation: 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.
authors.forename: Bing
authors.initials: B
authors.lastname: Tian
authors.affiliation: 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.
authors.forename: Allan R
authors.initials: AR
authors.lastname: Brasier
authors.affiliation: 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.
authors.forename: Jia
authors.identifier: 0000-0002-2811-1090
authors.initials: J
authors.lastname: Zhou
mesh_terms: D018797:Cell Cycle Proteins; D055808:Drug Discovery; D006801:Humans; D009687:Nuclear Proteins / Q000737:chemistry*; D014157:Transcription Factors / Q000737:chemistry*; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins