Bromodomain and extra-terminal domain proteins (BRD2, BRD3, BRD4, BRDT) (BET proteins)

The Bromodomain and Extra-Terminal (BET) family consists of four highly conserved proteins—BRD2, BRD3, BRD4, and BRDT—that function as epigenetic readers [1, 2, 15, 19]. These proteins contain two tandem bromodomains (BD1 and BD2) that specifically recognize and bind to acetylated lysine residues on histone tails and transcription factors [2, 7, 10, 18]. By recruiting transcriptional machinery, such as the positive transcription elongation factor b (P-TEFb) and the Mediator complex, BET proteins play a critical role in regulating the expression of genes involved in cell growth, apoptosis, and inflammation [1, 11, 15, 18]. In many cancers, BET proteins are dysregulated or hijacked to drive the overexpression of key oncogenes like MYC and BCL2, often through association with super-enhancers [9, 10, 13, 20]. Small-molecule BET inhibitors compete with acetylated histones for the bromodomain binding pockets, effectively displacing the proteins from chromatin and silencing oncogenic signaling pathways [5, 8, 12, 16]. While showing significant therapeutic promise in hematological malignancies and solid tumors, clinical development faces challenges including dose-limiting toxicities like thrombocytopenia and the emergence of drug resistance [1, 10, 16, 17]. Beyond oncology, BET proteins are also implicated in inflammatory diseases, viral infections, and metabolic disorders, making them versatile therapeutic targets [1, 3, 6, 19]. Recent advancements include the development of isoform-selective inhibitors and proteolysis-targeting chimeras (PROTACs) to improve efficacy and reduce off-target effects [13, 15, 17].

Other names

Bromodomain-containing protein 2Bromodomain-containing protein 3Bromodomain-containing protein 4Bromodomain testis-specific proteinRING3ORFXMCAPBRD2BRD3BRD4BRDTBET family

Competitive inhibition of bromodomain binding to acetylated lysine residues on histones and transcription factors, leading to displacement of BET proteins from chromatin and suppression of downstream oncogenic transcription (e.g., MYC) [1, 2, 5, 8, 10, 12, 13, 15, 16, 18, 20].