Bromodomain and extra-terminal domain protein (BET protein) (BET protein)

Bromodomain and extra-terminal domain (BET) proteins are a family of epigenetic readers that include BRD2, BRD3, BRD4, and the testis-specific BRDT [1, 2]. These proteins are characterized by two tandem bromodomains (BD1 and BD2) that recognize and bind to acetylated lysine residues on histone tails and other nuclear proteins [1, 3]. By serving as molecular scaffolds, BET proteins recruit transcriptional regulatory complexes, such as the Positive Transcription Elongation Factor b (P-TEFb) and the Mediator complex, to gene promoters and enhancers to facilitate RNA polymerase II-mediated transcription [2, 4]. In various diseases, particularly cancer, BET proteins are often hijacked to drive the expression of potent oncogenes like MYC, BCL2, and CDK6 [4, 5]. Small-molecule BET inhibitors work by competitively binding to the acetyl-lysine recognition pocket, thereby displacing BET proteins from chromatin and suppressing the transcription of target genes [2, 6]. While these inhibitors have shown significant efficacy in preclinical models of hematologic and solid tumors, clinical development faces challenges such as dose-limiting thrombocytopenia and gastrointestinal toxicities [4, 7]. Additionally, BET proteins play roles in inflammatory responses by regulating the expression of pro-inflammatory cytokines, making them targets for autoimmune and cardiovascular conditions [2, 8].

Other names

BET familyBromodomain-containing proteinBRD proteinBRD2/3/4/T

Competitive inhibition of the bromodomain acetyl-lysine binding pocket, preventing chromatin recruitment and subsequent transcriptional elongation of target genes.