2. Academic Validation
  3. Small Molecule Inhibitor of CBFβ-RUNX Binding for RUNX Transcription Factor Driven Cancers

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.
Anuradha Illendula 1,  Jane Gilmour 2,  Jolanta Grembecka 3,  Venkata Sesha Srimath Tirumala 1,  Adam Boulton 1,  Aravinda Kuntimaddi 1,  Charles Schmidt 1,  Lixin Wang 4,  John A Pulikkan 5,  Hongliang Zong 6,  Mahmut Parlak 7,  Cem Kuscu 7,  Anna Pickin 2,  Yunpeng Zhou 1,  Yan Gao 1,  Lauren Mishra 8,  Mazhar Adli 7,  Lucio H Castilla 5,  Roger A Rajewski 9,  Kevin A Janes 4,  Monica L Guzman 6,  Constanze Bonifer 2,  John H Bushweller 1
Affiliations

Affiliations

  • 1 Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.
  • 2 School of Cancer Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham, UK.
  • 3 Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • 4 Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
  • 5 Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
  • 6 Division of Hematology/Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, NY, USA.
  • 7 Department of Biochemistry, University of Virginia, Charlottesville, VA, USA.
  • 8 Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA.
  • 9 Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA.
PMID: 27428424 DOI: 10.1016/j.ebiom.2016.04.032
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.

Keywords

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

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-138617
    98.93%, CBFβ-RUNX 抑制剂
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