1. BET bromodomain inhibition as a therapeutic strategy to target c-Myc.
- Author
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Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, Chesi M, Schinzel AC, McKeown MR, Heffernan TP, Vakoc CR, Bergsagel PL, Ghobrial IM, Richardson PG, Young RA, Hahn WC, Anderson KC, Kung AL, Bradner JE, and Mitsiades CS
- Subjects
- Animals, Antineoplastic Agents chemistry, Azepines chemistry, Azepines pharmacology, Benzodiazepines chemistry, Benzodiazepines pharmacology, Cell Line, Tumor, Disease Models, Animal, Humans, Mice, Nuclear Proteins chemistry, Nuclear Proteins genetics, Nuclear Proteins metabolism, Protein Structure, Tertiary, Proto-Oncogene Proteins c-myc genetics, Transcriptional Activation drug effects, Triazoles chemistry, Triazoles pharmacology, Antineoplastic Agents pharmacology, Drug Discovery, Multiple Myeloma drug therapy, Proto-Oncogene Proteins c-myc antagonists & inhibitors
- Abstract
MYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective, we have targeted MYC transcription by interfering with chromatin-dependent signal transduction to RNA polymerase, specifically by inhibiting the acetyl-lysine recognition domains (bromodomains) of putative coactivator proteins implicated in transcriptional initiation and elongation. Using a selective small-molecule bromodomain inhibitor, JQ1, we identify BET bromodomain proteins as regulatory factors for c-Myc. BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of Myc-dependent target genes. In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell-cycle arrest and cellular senescence. Efficacy of JQ1 in three murine models of multiple myeloma establishes the therapeutic rationale for BET bromodomain inhibition in this disease and other malignancies characterized by pathologic activation of c-Myc., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
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