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EBioMedicine. 2016 Jun;8:117-131. doi: 10.1016/j.ebiom.2016.04.032. Epub 2016 Apr 29.

Small Molecule Inhibitor of CBFβ-RUNX Binding for RUNX Transcription Factor Driven Cancers.

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Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.
School of Cancer Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham, UK.
Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
Division of Hematology/Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, NY, USA.
Department of Biochemistry, University of Virginia, Charlottesville, VA, USA.
Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA.
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA.


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 CBFβ binding partner. CBFβ enhances DNA binding of RUNX subunits by relieving auto-inhibition. Both RUNX1 and CBFβ 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 CBFβ 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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