Gene expression is controlled through access to DNA, which is mediated by epigenetic modifications to histones.^1,2  Bromodomain and extra-terminal motif (BET) proteins are epigenetic “readers” that bind to acetylated lysine residues on histone tails.^3,4 BET proteins regulate initiation and continuation of transcription of key cell cycle control genes by recruiting and interacting with transcription factors and
RNA polymerase II.^5-7

Additionally, BET proteins can “bookmark” genes by remaining bound to chromatin during mitosis, thereby speeding reinitiation of transcription.⁵ Super-enhancers, which are noncoding regions of DNA critical to oncogene transcription and maintenance of cancer cell identity, are observed to have high densities of BET binding.⁸

Preclinical studies suggest that inhibition of BET may result in the downregulation of key cell cycle regulatory genes, cell cycle arrest, and apoptosis of tumor cells.^4,9

BMS is investigating BET inhibitors for the treatment of solid tumors and hematologic malignancies.