Bromodomains, a group of structurally similar proteins, serve as epigenetic “readers”— they recognize and bind acetylated lysine residues. The human body’s 40-plus bromodomains play a wide range of roles, including signal transduction in inflammatory pathways and transcription mediation.1
Instead of widespread downregulation with severe toxicity, the activity of JQ1 was contextual and specific to a small number of genes, suggesting that BET inhibitors could be a viable reality. Since then, the landscape has become increasingly active.
At present, at least 10 BET inhibitors are under investigation, with over a dozen active clinical trials.5
Early research suggested that BET inhibitors would have the most impact on hematologic malignancies, but clinical trials show that restricted doses may be necessary for safety, particularly due to thrombocytopenia. This has triggered development of a second generation of BET inhibitors, which are more selective for particular bromodomains. These agents appear to be better tolerated but may be more specific to certain cancer types.6
Figure. Impact of BET Inhibitors on Cancer Pathways
Ac indicates acetylation; BET, bromodomain and extra-terminal; BD, bromodomain; BRD, bromodomain-containing proteins; CTM, C-terminal motif; ET, extraterminal; NPS, N-terminal cluster of phosphorylation sites; P, phosphorylation.
The BET family members are “readers” of acetylated lysines that activate the transcription of aberrant genes, leading to carcinogenic processes affecting the cell cycle, proliferation, stemness properties, metastatic spreading, and angiogenesis. Inhibition of BET activity is believed to disrupt these processes.
Ocaña A, Nieto-Jiménez C, Pandiella A. Oncotarget. 2017;8(41):71285-71291. doi: 10.18632/oncotarget.19744.
Mechanisms of Action
BET inhibitors competitively bind bromodomains on a BET protein, thereby blocking localization to chromatin, which in turn suppresses recruitment of transcriptional proteins and resultant neoplastic processes.7
These processes include angiogenesis, cell cycle control, cancer stem cells, proliferation, metabolism, and metastasis11,12
). Studies have shown that BET inhibitors alter numerous pathways and expression of hundreds of genes, including MYC
, and cyclin D family genes. Emerging key areas of interest in BET inhibitor research include aspects of MYC
downregulation and angiogenic control.
BET inhibitors gained early recognition by downregulating MYC
, a known oncogenic driver in most human cancers.13 MYC
amplification promotes cell survival and division through induction of multiple pathways. Hematologic malignancies, in particular, are characterized by pathologic activation of c-Myc, an oncoprotein. Outside of transgenic models, c-Myc inhibition was unknown prior to the introduction of JQ1.
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