Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 11, Pages 4533-4558Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b01761
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Funding
- National Institutes of Health [P30 DA028821, R01 DA038446, T32 DA07287]
- Sanofi Innovation Awards (iAwards) Program
- Breast Cancer Research Program Breakthrough Award from the Department of Defense [BC160038]
- Cancer Prevention Research Institute of Texas award
- R. A. Welch Foundation Chemistry and Biology Collaborative Grant from the Gulf Coast Consortia
- John Sealy Memorial Endowment Fund
- Institute for Translational Sciences
- Sealy Center for Molecular Medicine
- Center for Addiction Research at UTMB
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BRD4, the most extensively studied member of the BET family, is an epigenetic regulator that localizes to DNA via binding to acetylated histories 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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