title: Small Molecule Inhibitor of CBFβ-RUNX Binding for RUNX Transcription Factor Driven Cancers.
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.
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Illendula
authors.affiliation: School of Cancer Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Gilmour
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Grembecka
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.
authors.forename: Venkata Sesha Srimath
authors.initials: VSS
authors.lastname: Tirumala
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Boulton
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.
authors.forename: Aravinda
authors.initials: A
authors.lastname: Kuntimaddi
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Schmidt
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Pulikkan
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, NY, USA.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Zong
authors.affiliation: Department of Biochemistry, University of Virginia, Charlottesville, VA, USA.
authors.forename: Mahmut
authors.initials: M
authors.lastname: Parlak
authors.affiliation: Department of Biochemistry, University of Virginia, Charlottesville, VA, USA.
authors.forename: Cem
authors.initials: C
authors.lastname: Kuscu
authors.affiliation: School of Cancer Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Pickin
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Mishra
authors.affiliation: Department of Biochemistry, University of Virginia, Charlottesville, VA, USA.
authors.forename: Mazhar
authors.initials: M
authors.lastname: Adli
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Lucio H
authors.initials: LH
authors.lastname: Castilla
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Rajewski
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Janes
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, NY, USA.
authors.forename: Monica L
authors.initials: ML
authors.lastname: Guzman
authors.affiliation: School of Cancer Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham, UK.
authors.forename: Constanze
authors.initials: C
authors.lastname: Bonifer
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Bushweller
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D050657:Core Binding Factor alpha Subunits / Q000737:chemistry / Q000378:metabolism*; D050658:Core Binding Factor beta Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D007938:Leukemia; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D050657:Core Binding Factor alpha Subunits; D050658:Core Binding Factor beta Subunit
keywords: CBFβ; Leukemia; PPI; RUNX; Transcription factor inhibitor; Triple negative breast cancer