Bromodomain and extra-terminal domain family second bromodomain (BET BD2) (BET BD2)

The Bromodomain and extra-terminal (BET) family of proteins, comprising BRD2, BRD3, BRD4, and BRDT, are essential epigenetic readers that facilitate gene transcription by recognizing acetylated lysine residues on histones (UniProt O60885). Each member of this family possesses two tandem bromodomains, known as BD1 and BD2, which serve distinct functional roles in the assembly of transcriptional complexes. BD1 is generally associated with the initiation of transcription, whereas BD2 is critical for transcriptional elongation and the recruitment of the positive transcription elongation factor b (P-TEFb) complex (Gilan et al., 2020, Science). Research has shown that selective inhibition of the BD2 domain can modulate specific pathological gene expressions, particularly those involved in inflammatory responses and oncogenic signaling, while sparing many of the housekeeping functions regulated by BD1 (Faivre et al., 2020, Nature). This selectivity is a key pharmacological strategy intended to mitigate the systemic toxicities, such as thrombocytopenia and gastrointestinal distress, frequently observed with pan-BET inhibitors (Piha-Paul et al., 2019). Consequently, BD2-selective inhibitors like apabetalone are being actively investigated for the treatment of diverse conditions, including major adverse cardiovascular events, chronic kidney disease, and various solid and hematological malignancies (ClinicalTrials.gov NCT02586441).

Other names

BET second bromodomainBD2 domain of BET proteinsBromodomain 2 of BRD2/BRD3/BRD4/BRDT

Selective competitive inhibition of the second bromodomain (BD2) of BET proteins, which prevents the recognition of acetylated lysine residues on histone tails and subsequently disrupts the recruitment of transcriptional machinery such as the positive transcription elongation factor b (P-TEFb) complex (Faivre et al., 2020, Nature).