Bromodomain and Extra-Terminal domain family bromodomain 1 (BET BD1)

The Bromodomain and Extra-Terminal (BET) family BD1 domains are the first of two tandem N-terminal acetyl-lysine binding modules found in the BET protein family, which includes BRD2, BRD3, BRD4, and the testis-specific BRDT [1]. These domains act as epigenetic readers that recognize acetylated lysine residues on histone tails and transcription factors, serving as a scaffold to recruit the Mediator complex and the Positive Transcription Elongation Factor b (P-TEFb) to promote gene transcription [2]. BD1 domains are particularly essential for the maintenance of oncogenic transcriptional programs, such as the expression of MYC, making them high-priority targets in oncology [3]. Dysregulation of BET-mediated transcription is implicated in various pathologies, including hematologic malignancies, solid tumors, and chronic inflammatory conditions [4]. Small-molecule inhibitors targeting the BD1 domain, such as the selective inhibitor GSK778 or pan-BET inhibitors like JQ1 and Molibresib, work by competitively binding the acetyl-lysine recognition pocket, thereby displacing BET proteins from chromatin and suppressing downstream gene expression [5]. Recent therapeutic strategies emphasize BD1-selective inhibition to potentially mitigate the dose-limiting toxicities, such as thrombocytopenia and gastrointestinal distress, often observed with non-selective pan-BET inhibition [6]. Sources: [1] UniProt (O60885, P25440); [2] Gilan et al., Science (2020); [3] Cochran et al., Nature Reviews Drug Discovery (2019); [4] Faivre et al., Science (2020); [5] ClinicalTrials.gov (NCT04293094); [6] Piha-Paul et al., Clinical Cancer Research (2019).

Other names

BET BD1First bromodomain of BET proteinsBromodomain 1 of Bromodomain and Extra-Terminal domain familyBD1 domain

Competitive inhibition of acetylated lysine binding to the bromodomain pocket, preventing the recruitment of transcriptional machinery to chromatin.