51. Small Molecule Inhibitor of CBFβ-RUNX Binding for RUNX Transcription Factor Driven Cancers
- Author
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Lauren Mishra, Mahmut Parlak, Adam Boulton, Cem Kuscu, Venkata Sesha Srimath Tirumala, Mazhar Adli, Yunpeng Zhou, John H. Bushweller, Anuradha Illendula, Yan Gao, Anna Pickin, Charles Schmidt, Jane Gilmour, Kevin A. Janes, John Anto Pulikkan, Roger A. Rajewski, Aravinda Kuntimaddi, Jolanta Grembecka, Lucio H. Castilla, Hongliang Zong, Constanze Bonifer, Monica L. Guzman, and Lixin Wang
- Subjects
0301 basic medicine ,Core Binding Factor alpha Subunits ,PPI ,lcsh:Medicine ,Biology ,Core binding factor ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,chemistry.chemical_compound ,Medicine, General & Internal ,hemic and lymphatic diseases ,medicine ,Triple negative breast cancer ,Transcription factor ,Gene ,Triple-negative breast cancer ,lcsh:R5-920 ,Leukemia ,CBFβ ,lcsh:R ,General Medicine ,medicine.disease ,Molecular biology ,RUNX ,3. Good health ,Cell biology ,030104 developmental biology ,RUNX1 ,chemistry ,Stem cell ,Transcription factor inhibitor ,lcsh:Medicine (General) - 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.
- Published
- 2016