Department of Molecular, Cell and Cancer Biology; UMass Metabolic Network
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.
CBFβ, Leukemia, PPI, RUNX, Transcription factor inhibitor, Triple negative breast cancer
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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/).
DOI of Published Version
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
Illendula A, Pulikkan JA, Castilla LH, Bushweller JH. (2016). Small Molecule Inhibitor of CBFbeta-RUNX Binding for RUNX Transcription Factor Driven Cancers. Open Access Articles. https://doi.org/10.1016/j.ebiom.2016.04.032. Retrieved from https://escholarship.umassmed.edu/oapubs/2819
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