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

Anuradha Illendula, Jane Gilmour, Jolanta Grembecka, Venkata Sesha Srimath Tirumala, Adam Boulton, Aravinda Kuntimaddi, Charles Schmidt, Lixin Wang, John A. Pulikkan, Hongliang Zong, Mahmut Parlak, Cem Kuscu, Anna Pickin, Yunpeng Zhou, Yan Gao, Lauren Mishra, Mazhar Adli, Lucio H. Castilla, Roger A. Rajewski, Kevin A. JanesMonica L. Guzman, Constanze Bonifer, John H. Bushweller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)117-131
Number of pages15
JournalEBioMedicine
Volume8
DOIs
StatePublished - Jun 1 2016
Externally publishedYes

Keywords

  • CBFβ
  • Leukemia
  • PPI
  • RUNX
  • Transcription factor inhibitor
  • Triple negative breast cancer

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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