Bromodomain and extra-terminal domain protein (BET) (BET)

Bromodomain and extra-terminal domain (BET) proteins, comprising BRD2, BRD3, BRD4, and BRDT, are critical epigenetic readers that regulate gene transcription by binding to acetylated lysine residues on histone tails and transcription factors (UniProt P21675). These proteins serve as scaffolds to recruit transcriptional machinery, including the Positive Transcription Elongation Factor b (P-TEFb) and RNA polymerase II, thereby facilitating the expression of genes essential for cell growth and survival (PubMed: 24469055). In various cancers, BET proteins are often hijacked to drive the overexpression of potent oncogenes such as MYC, BCL2, and CDK6 (PubMed: 31511301). Small molecule inhibitors like BMS-986158 (mivebresib) are designed to competitively bind to the acetyl-lysine recognition pockets of BET bromodomains, displacing the proteins from chromatin and suppressing oncogenic signaling (PubChem CID 118525141). Despite their therapeutic potential in hematologic and solid tumors, the broad regulatory role of BET proteins in normal physiology often results in dose-limiting toxicities, most notably thrombocytopenia and gastrointestinal distress (ClinicalTrials.gov: NCT02419417).

Other names

Bromodomain-containing proteinBET familyBRD proteinsBET reader proteins

Competitive inhibition of the bromodomain acetyl-lysine binding pocket, which displaces BET proteins from chromatin and prevents the recruitment of transcriptional machinery to oncogenic promoters (PubMed: 24469055).