Zhiqing Liu†, Pingyuan Wang†, Haiying Chen†, Eric A. Wold†, Bing Tian‡§ξ, Allan R. Brasier‡§ξ, and Jia Zhou*†§ξ

J. Med. Chem., 2017, 60 (11), pp 4533–4558

DOI: 10.1021/acs.jmedchem.6b01761

Publication Date (Web): February 14, 2017

Copyright © 2017 American Chemical Society

 

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.

 

(Table is as of November 2016, article from Feb 2017)

 

(1),(32) I-BET762/GSK-525762A (2),(33) OTX-015/MK8628 (3),(34) CPI-0610 (4),(35) TEN-010 (5),(36) and ABBV-075 (6).(37) Most of their clinical investigations are focused on cancer therapies.