Faculty Collaboration Database

Small Molecule Inhibitor of CBFβ-RUNX Binding for RUNX Transcription Factor Driven Cancers. EBioMedicine 2016 Jun;8:117-131

Date

07/20/2016

Pubmed ID

27428424

Pubmed Central ID

PMC4919611

DOI

10.1016/j.ebiom.2016.04.032

Scopus ID

2-s2.0-84966769195 (requires institutional sign-in at Scopus site)   73 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.

Author List

Illendula A, Gilmour J, Grembecka J, Tirumala VSS, Boulton A, Kuntimaddi A, Schmidt C, Wang L, Pulikkan JA, Zong H, Parlak M, Kuscu C, Pickin A, Zhou Y, Gao Y, Mishra L, Adli M, Castilla LH, Rajewski RA, Janes KA, Guzman ML, Bonifer C, Bushweller JH

Author

John A. Pulikkan PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

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