Bromodomain-containing protein 2, Bromodomain-containing protein 3, and Bromodomain-containing protein 4 (BRD2/3/4)

The BRD2, BRD3, and BRD4 bromodomains are key components of the Bromodomain and Extra-Terminal (BET) family of epigenetic reader proteins [2, 5]. These proteins contain two highly conserved N-terminal bromodomains (BD1 and BD2) that specifically recognize and bind to acetylated lysine residues on histone tails and various transcription factors [5, 9]. By acting as molecular scaffolds, they recruit essential transcriptional machinery, such as the positive transcription elongation factor complex (P-TEFb), to gene promoters and super-enhancers, thereby facilitating RNA polymerase II-mediated transcription [1, 4]. In many pathological states, particularly in hematological and solid malignancies, BET proteins are dysregulated and drive the overexpression of critical oncogenes like MYC and BCL2 [3, 10]. Small-molecule BET inhibitors (BETi) are designed to competitively bind the acetyl-lysine binding pocket of these bromodomains, leading to the displacement of BET proteins from chromatin and the subsequent suppression of pro-proliferative and pro-inflammatory gene programs [6, 9]. Clinical development of these inhibitors has targeted a wide range of conditions, including NUT midline carcinoma, acute myeloid leukemia, and various inflammatory diseases [17, 22]. However, dose-limiting toxicities such as thrombocytopenia and gastrointestinal distress remain significant challenges in their therapeutic application [13, 18]. Additionally, these proteins play roles in maintaining mitotic memory and regulating metabolic pathways, expanding their potential as targets beyond oncology [15, 23].

Other names

BET proteinsBromodomain and extra-terminal domain proteinsBET familyEpigenetic readers

Competitive inhibition of acetyl-lysine binding to the bromodomain pocket, leading to the displacement of BET proteins from chromatin and suppression of target gene transcription [3, 4, 9].