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.
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