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

The second bromodomain (BD2) of the Bromodomain and Extra-Terminal (BET) family proteins—comprising BRD2, BRD3, BRD4, and BRDT—is a specialized epigenetic reader module that recognizes acetylated lysine residues on histone tails and various transcription factors (Source: UniProt, PubMed PMID: 32075868). While the first bromodomain (BD1) is primarily associated with the maintenance of steady-state gene expression and cell cycle progression, BD2 is specifically involved in the rapid induction of genes, particularly those associated with inflammatory responses and specific oncogenic pathways (Source: Nature, 2020, 578(7794):296-301). Therapeutic targeting of BD2 has gained significant interest as a strategy to improve the safety profile of BET inhibitors, as pan-BET inhibitors often cause dose-limiting toxicities such as thrombocytopenia and gastrointestinal distress (Source: Clinical Cancer Research, 2020). BD2-selective inhibitors, such as apabetalone and ABBV-744, are being evaluated in clinical trials for their efficacy in treating cardiovascular disease, chronic kidney disease, and advanced malignancies like prostate cancer (Source: Journal of Medicinal Chemistry, 2020). By competitively binding to the acetyl-lysine pocket of BD2, these drugs prevent the recruitment of the transcriptional machinery to specific genomic loci, thereby downregulating key drivers of disease such as MYC and pro-inflammatory cytokines (Source: NIH, PubChem). This selective approach aims to provide a wider therapeutic window compared to first-generation pan-BET inhibitors by sparing the BD1-dependent functions essential for normal cell homeostasis.

Other names

C-terminal bromodomain of BET proteinsBromodomain-containing protein second bromodomainBET-BD2BET BD2 domain

Competitive inhibition of the acetyl-lysine binding pocket of the second bromodomain (BD2) in BET proteins, preventing the recruitment of transcriptional co-activators and RNA polymerase II to specific gene promoters (Source: PubMed PMID: 32075868).