Bromodomain-containing protein 2, 3, and testis-specific second bromodomain (BET BD2) (BET BD2)

The second bromodomain (BD2) of the Bromodomain and Extra-Terminal (BET) family proteins, including Bromodomain-containing protein 2 (BRD2), Bromodomain-containing protein 3 (BRD3), and Bromodomain testis-specific protein (BRDT), functions as an epigenetic reader that identifies acetylated lysine residues on histone tails (UniProt P25440, Q15059, Q58F21). These domains are essential for the assembly of transcriptional complexes at specific chromatin sites, particularly those associated with inflammatory and oncogenic gene expression (Faivre et al., 2020, Nature). While the first bromodomain (BD1) is primarily linked to general cell cycle regulation, BD2 is more specifically involved in the maintenance of pathological gene programs in cancer and chronic inflammation (Gilham et al., 2016, J. Cardiovasc. Transl. Res.). Therapeutic targeting of the BD2 domain has emerged as a strategy to improve the safety profile of BET inhibitors, as pan-BET inhibition is often limited by toxicities like thrombocytopenia. Selective BD2 inhibitors, such as ABBV-744 and Apabetalone, work by competitively binding the acetyl-lysine pocket, thereby displacing the BET proteins from chromatin and suppressing the transcription of downstream targets like MYC (PubChem CID 46215266). This targeted approach is currently being investigated for its efficacy in treating hematologic malignancies, solid tumors, and cardiovascular diseases.

Other names

BET BD2Bromodomain-containing protein 2/3/T second bromodomainBRD2-BD2BRD3-BD2BRDT-BD2BET family second bromodomain

Competitive inhibition of acetyl-lysine binding to the second bromodomain (BD2) of BET proteins, leading to the displacement of these proteins from chromatin and the downregulation of target genes such as MYC and inflammatory cytokines (Faivre et al., 2020, Nature).