BRD4: From molecular understanding to therapeutics development.

Bromodomain-containing protein 4 (BRD4) is an important therapeutic target for anticancer, antiviral, and anti-inflammatory responses. Although its role in transcription, chromatin dynamics, and epigenetic programs is well recognized, recent studies have expanded the functions of BRD4 and its related bromodomain and extra-terminal (BET) family members (BRD2, BRD3, and BRDT) to other molecular and biological processes. How a universal epigenetic regulator is tailored for context-specific gene/pathway regulation is mechanistically intriguing. In this review, we highlight the importance of protein isoforms and posttranslational modifications, particularly phosphorylation, in generating the protein diversity necessary for selective factor recruitment and context-dependent regulation. Three BRD4 protein isoforms have been identified, including the universally expressed BRD4-L and BRD4-S(a) (simplified as BRD4-S), representing the long and short isoform a, and cell-/stress-specific short isoform b, BRD4-S(b). A phospho-switch mechanism controlling the open/closed state of the bromodomain and BRD4 interaction with partner proteins will also be discussed. Mechanistic understanding of BET protein action has led not only to the development of diverse bromodomain-binding compounds currently used in clinical trials but also to the discovery of a new class of small-molecule inhibitors targeting an intrinsically disordered region (IDR) of phospho-BRD4 to alter specific protein-protein interaction (PPI) networks without globally perturbing transcription programs and chromatin landscapes, thus significantly reducing off-target effects and providing new directions for therapeutic drug development.