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BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc
Open accessAbstract
SUMMARY 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 co-activator 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.
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Selective inhibition of BET bromodomains
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Promiscuous Mutations Activate the Noncanonical NF-κB Pathway in Multiple Myeloma
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Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers
Lovén, J., Hoke, H. A., Lin, C. Y., Lau, A., Orlando, D. A., Vakoc, C. R., Bradner, J. E., Lee, T. I., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.03.036 · Cited by 2,961
Self-citationThe PI3K Pathway in Human Disease
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Phthalimide conjugation as a strategy for in vivo target protein degradation
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Metadata
- Authors
- Delmore, J. E., Issa, G. C., Lemieux, M. E., Rahl, P. B., Shi, J., Jacobs, H. M., Kastritis, E., Gilpatrick, T., Paranal, R. M., Qi, J., Chesi, M., Schinzel, A. C., McKeown, M. R., Heffernan, T. P., Vakoc, C. R., Bergsagel, P. L., Ghobrial, I. M., Richardson, P. G., Young, R. A., Hahn, W. C., Anderson, K. C., Kung, A. L., Bradner, J. E., & Mitsiades, C. S.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 146
- Issue
- 6
- Pages
- 904-917
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2120572492
- Cited by
- 2,813
- References
- 14
- FWCI
- 62.42
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Delmore, J. E., Issa, G. C., Lemieux, M. E., Rahl, P. B., Shi, J., Jacobs, H. M., Kastritis, E., Gilpatrick, T., Paranal, R. M., Qi, J., Chesi, M., Schinzel, A. C., McKeown, M. R., Heffernan, T. P., Vakoc, C. R., Bergsagel, P. L., Ghobrial, I. M., Richardson, P. G., Young, R. A., . . . Mitsiades, C. S. (2011). BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc. Cell. https://doi.org/10.1016/j.cell.2011.08.017
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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