Bromodomain and extra-terminal domain protein (BET protein)

Bromodomain and extra-terminal domain proteins (BET proteins) are a family of transcriptional regulators that function as epigenetic readers of acetylated lysine residues on histones and other proteins[1][4][7]. The canonical BET family consists of BRD2, BRD3, BRD4, and the testis-specific BRDT, each characterized by two tandem N-terminal bromodomains (BD1 and BD2) and a C-terminal extra-terminal (ET) domain[1][4][7]. BET proteins recruit transcription factors and coactivators, promote RNA polymerase II–dependent transcription, and regulate multiple chromatin-associated processes, including DNA repair and replication[1][3]. They play crucial roles in cell proliferation, development, inflammation, and oncogenesis, and pharmacological inhibition or selective degradation of BET proteins is a promising therapeutic strategy under exploration for various cancers, inflammatory diseases, and other pathology involving aberrant gene transcription[2][5][8]. Drugs targeting BET proteins disrupt their interaction with acetylated histones, leading to selective repression of key oncogenes such as c-MYC and inhibition of oncogenic fusion proteins like BRD4-NUT, offering clinical benefit in some settings[2][5][8]. Safety and resistance remain key therapeutic challenges, and biomarkers for patient stratification are under active investigation.

Other names

Bromodomain and extraterminal domain proteinBET family proteinBRD2/BRD3/BRD4/BRDT

Inhibition of bromodomain/acetyl-lysine interaction (competitive binding in the bromodomain pocket); Displacement of BET proteins from chromatin; Disruption of oncogenic transcriptional programs (e.g., c-MYC, NUT fusion); Selective degradation (by PROTACs/LYTACs)