Bromodomain and extra-terminal domain protein second bromodomain (BD2) of BRD2, BRD3, and BRD4 (BET BD2)

The Bromodomain and Extra-Terminal (BET) family proteins, specifically BRD2, BRD3, and BRD4, are essential epigenetic readers that facilitate gene transcription by recognizing acetylated lysine residues on histone tails (UniProt P25440, Q15059, O60885). These proteins possess two tandem bromodomains, BD1 and BD2, which exhibit distinct biological functions; BD1 is generally associated with the initiation of transcription, whereas BD2 is primarily involved in transcriptional elongation and the maintenance of gene expression programs (Gilan et al., 2020, Science). Targeting the BD2 domain specifically has become a significant focus in drug development to overcome the dose-limiting toxicities, such as thrombocytopenia and gastrointestinal distress, typically associated with pan-BET inhibitors (Faivre et al., 2020, Nature). BD2-selective inhibitors, such as apabetalone and ABBV-744, work by competitively binding to the BD2 pocket, thereby preventing the recruitment of transcriptional machinery to specific promoters and enhancers (ClinicalTrials.gov NCT02586441). This targeted approach is being explored for the treatment of diverse conditions, including cardiovascular disease, chronic kidney disease, and various malignancies, where it aims to modulate the expression of key drivers like MYC and pro-inflammatory cytokines (PubChem CID 46240344).

Other names

BET BD2Second bromodomain of BRD2/3/4Bromodomain-containing protein 2/3/4 BD2BET BD2 domains

Competitive inhibition of the binding of acetylated lysine residues on histone tails to the BD2 pocket, preventing the recruitment of transcriptional machinery to specific gene loci.