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

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


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.

Keywords: CBFβ; Leukemia; PPI; RUNX; Transcription factor inhibitor; Triple negative breast cancer.

MeSH terms

  • Allosteric Regulation / drug effects
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Line, Tumor
  • Core Binding Factor alpha Subunits / chemistry
  • Core Binding Factor alpha Subunits / metabolism*
  • Core Binding Factor beta Subunit / chemistry
  • Core Binding Factor beta Subunit / genetics
  • Core Binding Factor beta Subunit / metabolism*
  • Drug Discovery
  • Drug Screening Assays, Antitumor
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockdown Techniques
  • Humans
  • Leukemia
  • Models, Molecular
  • Molecular Conformation
  • Mutation
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Binding / drug effects
  • Protein Interaction Domains and Motifs
  • Protein Multimerization
  • Signal Transduction / drug effects
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Core Binding Factor alpha Subunits
  • Core Binding Factor beta Subunit