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Drug Discov Today Technol. 2016 Mar;19:45-50. doi: 10.1016/j.ddtec.2016.06.004. Epub 2016 Jul 21.

Clinical trials for BET inhibitors run ahead of the science.

Author information

1
Department of Medicine, Cancer Research Center, Boston University School of Medicine, Boston, MA 02118, United States.
2
Flow Cytometry Core Facility, Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, United States.
3
Department of Medicine, Cancer Research Center, Boston University School of Medicine, Boston, MA 02118, United States; Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, United States. Electronic address: gdenis@bu.edu.

Abstract

Several cancer clinical trials for small molecule inhibitors of BET bromodomain proteins have been initiated. There is enthusiasm for the anti-proliferative effect of inhibiting BRD4, one of the targets of these inhibitors, which is thought to cooperate with MYC, a long-desired target for cancer therapeutics. However, no current inhibitor is selective for BRD4 among the three somatic BET proteins, which include BRD2 and BRD3; their respective functions are partially overlapping and none are functionally redundant with BRD4. Each BET protein controls distinct transcriptional pathways that are important for functions beyond cancer cell proliferation, including insulin production, cytokine gene transcription, T cell differentiation, adipogenesis and most seriously, active repression of dangerous latent viruses like HIV. BET inhibitors have been shown to reactivate HIV in human cells. Failure to appreciate that at concentrations used, no available BET inhibitor is member-selective, or to develop a sound biological basis to understand the diverse functions of BET proteins before undertaking for these clinical trials is reckless and likely to lead to adverse events. More mechanistic information from new basic science studies should enable proper focus on the most relevant cancers and define the expected side effect profiles.

PMID:
27769357
PMCID:
PMC5116321
DOI:
10.1016/j.ddtec.2016.06.004
[Indexed for MEDLINE]
Free PMC Article

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