The Mitsubishi Tanabe Pharma Corporation first described thienodiazepine analogs that potently inhibit the closely related bromodomains of the BET family ( 6). BRD2 and BRD3 also regulate the transcription of growth-promoting genes, suggesting that the BET family has reinforcing roles to enable proper cell growth ( 5). Consistent with this model, experimental reduction of BRD4 levels or activity has been shown to cause profound effects on cell cycle progression and cellular viability ( 3, 4).
Functional studies have suggested that BRD4 plays an important role in the regulation of growth-associated genes at the M/G 1 boundary by retaining P-TEFb at the promoters of key regulatory genes throughout mitosis ( 3, 4). Through its interaction with BRD4, P-TEFb is recruited to promoters to phosphorylate the carboxyl-terminal domain of the large subunit of RNA polymerase II (RNAPII). BRD4 is a well-established regulator of P-TEFb, a complex consisting of cyclin-dependent kinase (CDK) 9 and cyclin T, among other polypeptides ( 2– 4). Members of the BET family, including BRD2, BRD3, BRD4, and BRDT, modulate gene expression by recruiting transcriptional regulators to specific genomic locations ( 1). The BET protein family employs tandem bromodomains to recognize specific acetylated lysine residues in the N-terminal tails of histone proteins ( 1). Such inhibitors may have clinical utility given the widespread pathogenetic role of MYC in cancer. These findings demonstrate that pharmacologic inhibition of MYC is achievable through targeting BET bromodomains. Treatment with a BET inhibitor resulted in significant antitumor activity in xenograft models of Burkitt's lymphoma and acute myeloid leukemia. MYC suppression was accompanied by deregulation of the MYC transcriptome, including potent reactivation of the p21 tumor suppressor. Exogenous expression of MYC from an artificial promoter that is resistant to BET regulation significantly protected cells from cell cycle arrest and growth suppression by BET inhibitors. Inhibition of BET bromodomain–promoter interactions and subsequent reduction of MYC transcript and protein levels resulted in G 1 arrest and extensive apoptosis in a variety of leukemia and lymphoma cell lines. MYC transcriptional suppression was observed in the context of the natural, chromosomally translocated, and amplified gene locus. Here, we demonstrate the rapid and potent abrogation of MYC gene transcription by representative small molecule inhibitors of the BET family of chromatin adaptors. However, pharmacologic inhibition of MYC function has proven challenging because of both the diverse mechanisms driving its aberrant expression and the challenge of disrupting protein–DNA interactions. The MYC transcription factor is a master regulator of diverse cellular functions and has been long considered a compelling therapeutic target because of its role in a range of human malignancies.
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