CHAPTER 9: Pharmacological Regulation and Functional Significance of Chromatin Binding by BET Tandem Bromodomains

Bromodomains are protein–protein interaction modules that recognize acetylated proteins and form acetylation-dependent complexes. Human bromodomains are encoded within nuclear proteins, often with enzymatic and/or protein/DNA-interaction domains. The bromodomain and extraterminal domain (BET) family is evolutionarily conserved and essential in yeast, fly, and mouse development. Humans encode four BET paralogues (BRDT, BRD2, BRD3, and BRD4) that contain two N-terminal bromodomains and a C-terminal extraterminal protein–protein interaction domain. BET bromodomain inhibitors modulate diverse transcriptional processes including cell cycle progression, lineage specification, and inflammation. Consequently, BET inhibitors are in clinical trials for hematological malignancies, solid tumors, and inflammation-driven diseases. However, clinical studies have identified dose-limiting toxicities associated with pan-BET inhibitors, thus hampering progress toward FDA approval. Compounds with selectivity toward the N- or C-terminal BET bromodomains have recently entered the clinic and exhibit differential and cell-type-specific transcriptional effects compared to pan-BET inhibitors. Compounds that degrade BET proteins or that bivalently bind to both the N- and C-terminal BET bromodomains have also been reported. However, the mechanisms linking different modes of BET inhibition to divergent transcriptional outputs are poorly understood. Better understanding of the protein–protein interaction targets and cooperative functions carried out by BET bromodomains would facilitate therapeutic application of BET inhibitors.