Bromodomain and extra-terminal domain family (BET)

The Bromodomain and Extra-Terminal (BET) domain family consists of four highly conserved epigenetic reader proteins: BRD2, BRD3, BRD4, and the testis-specific BRDT. These proteins are characterized by two tandem N-terminal bromodomains (BD1 and BD2) that specifically recognize and bind to acetylated lysine residues on histone tails and other nuclear proteins. By docking onto acetylated chromatin, BET proteins act as scaffolds to recruit transcriptional regulatory complexes, such as the positive transcription elongation factor b (P-TEFb) and the Mediator complex, to promote RNA polymerase II-dependent transcription. This mechanism is essential for regulating genes involved in cell cycle progression, proliferation, and the inflammatory response. In various diseases, particularly cancers and inflammatory conditions, BET proteins are often dysregulated and drive the aberrant expression of potent oncogenes like MYC and pro-inflammatory cytokines. Pharmacological targeting of the BET family using small-molecule inhibitors (BETi) has emerged as a promising therapeutic strategy. These inhibitors occupy the acetyl-lysine binding pocket of the bromodomains, effectively displacing BET proteins from chromatin and suppressing the transcriptional programs that sustain tumor growth and inflammation. While clinical trials have shown efficacy in hematologic malignancies and NUT midline carcinoma, therapeutic challenges include dose-limiting toxicities such as thrombocytopenia and the need for more selective inhibitors to improve the safety profile.

Other names

BET proteinsBET familyBromodomain-containing protein 2 (BRD2)Bromodomain-containing protein 3 (BRD3)Bromodomain-containing protein 4 (BRD4)Bromodomain testis-specific protein (BRDT)Ring3OrfxMcap

Competitive inhibition of the bromodomain binding to acetylated lysine residues on histone tails (primarily H3 and H4), which prevents the recruitment of transcriptional machinery such as P-TEFb and the Mediator complex, thereby downregulating the expression of key oncogenes and pro-inflammatory genes.