Bromodomain-containing protein 2 and Bromodomain-containing protein 4 (BRD2/BRD4)

Bromodomain-containing protein 2 (BRD2) and Bromodomain-containing protein 4 (BRD4) are key members of the Bromodomain and Extra-Terminal (BET) family of epigenetic readers [1, 4]. These proteins are characterized by two highly conserved N-terminal bromodomains (BD1 and BD2) that specifically recognize and bind to acetylated lysine residues on histone tails and other nuclear proteins [1, 9]. This interaction allows BRD2 and BRD4 to act as scaffolds, recruiting transcriptional machinery such as the positive transcription elongation factor b (P-TEFb) and mediator complexes to specific genomic regions [1, 2, 5]. By doing so, they drive the expression of genes essential for cell cycle progression, proliferation, and the inflammatory response [1, 2, 5]. In various diseases, particularly cancers like acute myeloid leukemia and NUT midline carcinoma, BRD4 is often dysregulated or involved in oncogenic fusions, leading to the constitutive activation of growth-promoting genes such as MYC [1, 8, 13]. Pharmacological targeting of these proteins using small-molecule BET inhibitors, which competitively block the bromodomain-acetyl-lysine interaction, has shown significant therapeutic potential [1, 8, 14]. These inhibitors induce growth arrest and apoptosis in tumor cells and suppress pro-inflammatory cytokine production [1, 8, 14]. However, clinical development faces challenges such as dose-limiting toxicities, including thrombocytopenia and gastrointestinal issues, due to the broad role of BET proteins in normal cellular transcription [8, 12, 13].

Other names

BRD2BRD4BET proteinsBromodomain-containing protein 2Bromodomain-containing protein 4RING3MCAPHUNK1Bromodomain-containing protein 2/4

Competitive inhibition of bromodomain binding to acetylated lysine residues on histones, leading to displacement of BET proteins from chromatin and suppression of oncogenic transcription (e.g., MYC) [1, 8, 13]