Novel strategies targeting bromodomain-containing protein 4 (BRD4) for cancer drug discovery

Abstract

As epigenetic readers of the histone code, BRD4 is the most extensively and thoroughly studied member of BET family, which plays a critical role in many human diseases including cancer, inflammation, HIV infections, CNS disorders, and cardiovascular diseases and has been proved to be a promising therapeutic target for these diseases. To date, many small-molecule BRD4 inhibitors have been discovered, and some of them are in clinical trials for the treatment of different diseases. Due to the lack of selectivity of these small molecules for BRD4 BD1, BRD4 BD2 and/or other BET proteins, they exert some toxic side effects, including dizziness, nausea, and vomit. Now, novel strategies are urgent needed to improve the selectivity and reduce the side effects of current BRD4 inhibitors. Herein, in this article, we made a summary of the recent development of novel strategies targeting BRD4. Opportunities for these strategies to achieve selective and efficacious BRD4 inhibitors for treating human diseases are also highlighted.

Keywords: BRD4; Bivalent inhibitors; Dual target inhibitors; Epigenetic readers; KAc; PTOTACs.