Bromodomain and Extra-Terminal domain second bromodomain (BET BD2) (BET BD2)

The Bromodomain and Extra-Terminal (BET) family proteins, including BRD2, BRD3, BRD4, and BRDT, contain two distinct N-terminal bromodomains known as BD1 and BD2 (UniProt, 2024). These domains act as epigenetic readers that recognize acetylated lysine residues on histone tails and transcription factors, facilitating the assembly of transcriptional complexes (PubMed, PMC7354504). While BD1 is primarily associated with the regulation of the cell cycle and oncogenes like MYC, the BD2 domain is specifically involved in the induction of inflammatory and metabolic gene programs (Nature, 2020, 580(7804)). Selective inhibition of the BD2 domain has emerged as a therapeutic strategy to maintain efficacy in treating inflammatory and cardiovascular diseases while minimizing the dose-limiting toxicities, such as thrombocytopenia, typically observed with pan-BET or BD1-selective inhibitors (Journal of Medicinal Chemistry, 2022, 65(1)). Drugs targeting BD2, such as apabetalone (RVX-208), are being investigated for their potential to reduce major adverse cardiovascular events by modulating alkaline phosphatase and C-reactive protein levels (ClinicalTrials.gov, NCT02586441). By competitively binding to the acetyl-lysine recognition pocket of BD2, these inhibitors disrupt the recruitment of BET proteins to specific genomic loci, thereby downregulating pathological gene expression (Science, 2020, 368(6489)).

Other names

BET BD2Bromodomain and Extra-Terminal domain 2C-terminal bromodomain of BET proteinsBD2 domain

Competitive inhibition of acetylated lysine binding to the BD2 pocket of BET proteins, disrupting the recruitment of transcriptional complexes to chromatin.