Bromodomain and extra-terminal domain proteins 2, 3, and 4 (BRD2/BRD3/BRD4)

The Bromodomain and Extra-Terminal (BET) family, specifically BRD2, BRD3, and BRD4, consists of essential epigenetic reader proteins that recognize acetylated lysine residues on histone tails and various transcription factors [1, 6]. These proteins function as molecular scaffolds that recruit transcriptional regulatory complexes, most notably the positive transcription elongation factor b (P-TEFb), to chromatin to facilitate RNA polymerase II-mediated gene transcription and elongation [3, 11]. In pathological states such as cancer and chronic inflammation, BET proteins are often dysregulated, leading to the aberrant overexpression of key oncogenes like MYC and BCL2, as well as pro-inflammatory cytokines [2, 4, 10]. Small-molecule BET inhibitors are designed to competitively bind the conserved N-terminal bromodomains (BD1 and BD2), effectively displacing the BET proteins from chromatin and suppressing disease-driving transcriptional programs [7, 12]. While these inhibitors have shown significant therapeutic potential in clinical trials for malignancies like NUT midline carcinoma and acute myeloid leukemia, their development is frequently challenged by dose-limiting toxicities, particularly thrombocytopenia, which arises from the inhibition of BET-dependent megakaryocyte differentiation [9, 10, 13].

Other names

BET family proteinsBromodomain-containing protein 2Bromodomain-containing protein 3Bromodomain-containing protein 4RING3FSHMCAPHUNK1ORFX

Competitive inhibition of the bromodomain acetyl-lysine binding pocket, preventing the binding of BET proteins to acetylated histones and non-histone proteins, thereby disrupting the recruitment of transcriptional machinery (such as P-TEFb) and suppressing the expression of oncogenes and inflammatory genes.