Small Molecule Inhibitor of CBFbeta-RUNX Binding for RUNX Transcription Factor Driven Cancers
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Journal ArticlePublication Date
2016-06-01Keywords
CBFβLeukemia
PPI
RUNX
Transcription factor inhibitor
Triple negative breast cancer
Cancer Biology
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Transcription factors have traditionally been viewed with skepticism as viable drug targets, but they offer the potential for completely novel mechanisms of action that could more effectively address the stem cell like properties, such as self-renewal and chemo-resistance, that lead to the failure of traditional chemotherapy approaches. Core binding factor is a heterodimeric transcription factor comprised of one of 3 RUNX proteins (RUNX1-3) and a CBFbeta binding partner. CBFbeta enhances DNA binding of RUNX subunits by relieving auto-inhibition. Both RUNX1 and CBFbeta are frequently mutated in human leukemia. More recently, RUNX proteins have been shown to be key players in epithelial cancers, suggesting the targeting of this pathway could have broad utility. In order to test this, we developed small molecules which bind to CBFbeta and inhibit its binding to RUNX. Treatment with these inhibitors reduces binding of RUNX1 to target genes, alters the expression of RUNX1 target genes, and impacts cell survival and differentiation. These inhibitors show efficacy against leukemia cells as well as basal-like (triple-negative) breast cancer cells. These inhibitors provide effective tools to probe the utility of targeting RUNX transcription factor function in other cancers.Source
EBioMedicine. 2016 Jun;8:117-31. doi: 10.1016/j.ebiom.2016.04.032. Epub 2016 Apr 29. Link to article on publisher's site
DOI
10.1016/j.ebiom.2016.04.032Permanent Link to this Item
http://hdl.handle.net/20.500.14038/40011PubMed ID
27428424Notes
Full author list omitted for brevity. For full list of authors see article.
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Copyright © 2016 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Distribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1016/j.ebiom.2016.04.032
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Except where otherwise noted, this item's license is described as Copyright © 2016 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).