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


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          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.

          Graphical Abstract


          • Small molecule inhibitors of CBFβ-RUNX protein-protein interaction developed.

          • Inhibitors alter occupancy of RUNX1 on target genes and alter their expression.

          • Inhibitors show efficacy against leukemia cell lines and basal-like (triple negative) breast cancer cell lines.

          Transcription factors are proteins that bind to DNA and regulate how much of other proteins are made. We describe the development of inhibitors of the interaction between two transcription factors, CBFβ and RUNX. Both these transcription factors are the targets of alterations in human leukemia as well as in a number of solid tumors. The inhibitor changes the behavior of the RUNX transcription factor and alters the levels of proteins it regulates. We show these inhibitors may have potential utility for leukemia as well as one specific type of breast cancer which has a very poor prognosis.

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          Most cited references37

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          Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures.

          The three-dimensional culture of MCF-10A mammary epithelial cells on a reconstituted basement membrane results in formation of polarized, growth-arrested acini-like spheroids that recapitulate several aspects of glandular architecture in vivo. Oncogenes introduced into MCF-10A cells disrupt this morphogenetic process, and elicit distinct morphological phenotypes. Recent studies analyzing the mechanistic basis for phenotypic heterogeneity observed among different oncogenes (e.g., ErbB2, cyclin D1) have illustrated the utility of this three-dimensional culture system in modeling the biological activities of cancer genes, particularly with regard to their ability to disrupt epithelial architecture during the early aspects of carcinoma formation. Here we provide a collection of protocols to culture MCF-10A cells, to establish stable pools expressing a gene of interest via retroviral infection, as well as to grow and analyze MCF-10A cells in three-dimensional basement membrane culture.
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            Small-molecule inhibitors of protein-protein interactions: progressing toward the reality.

            The past 20 years have seen many advances in our understanding of protein-protein interactions (PPIs) and how to target them with small-molecule therapeutics. In 2004, we reviewed some early successes; since then, potent inhibitors have been developed for diverse protein complexes, and compounds are now in clinical trials for six targets. Surprisingly, many of these PPI clinical candidates have efficiency metrics typical of "lead-like" or "drug-like" molecules and are orally available. Successful discovery efforts have integrated multiple disciplines and make use of all the modern tools of target-based discovery-structure, computation, screening, and biomarkers. PPIs become progressively more challenging as the interfaces become more complex, i.e., as binding epitopes are displayed on primary, secondary, or tertiary structures. Here, we review the last 10 years of progress, focusing on the properties of PPI inhibitors that have advanced to clinical trials and prospects for the future of PPI drug discovery.
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              A common precursor for hematopoietic and endothelial cells.

              Embryonic stem cell-derived embryoid bodies contain a unique precursor population which, in response to vascular endothelial growth factor, gives rise to blast colonies in semi-solid medium. Upon transfer to liquid culture with appropriate cytokines, these blast colonies generate both hematopoietic and adherent, stromal-type cells. Cells within the adherent population display characteristics of endothelial lineage including the expression of CD31, flk-1, flt-1, tie-2, the capacity to take up acetylated LDL and the presence of cytoplasmic Weibel-Palade bodies. Mixing studies demonstrated that the hematopoietic and endothelial precursors within the blast colonies develop from the same cell, the blast colony-forming cell. Kinetic analysis showed that the blast colony-forming cell represents a transient cell population that develops early and is lost quickly during embryoid body development. These findings provide strong evidence that the blast colony-forming cell represents the long-hypothesized hemangioblast, the common precursor of the hematopoietic and endothelial lineages.

                Author and article information

                29 April 2016
                June 2016
                29 April 2016
                : 8
                : 117-131
                [a ]Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA
                [b ]School of Cancer Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham, UK
                [c ]Department of Pathology, University of Michigan, Ann Arbor, MI, USA
                [d ]Division of Hematology/Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, NY, USA
                [e ]Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
                [f ]Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA
                [g ]Department of Biochemistry, University of Virginia, Charlottesville, VA, USA
                [h ]Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA
                [i ]Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA
                Author notes
                [* ]Corresponding author.

                These authors contributed equally to this work.

                © 2016 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                : 14 January 2016
                : 12 April 2016
                : 25 April 2016
                Research Paper

                cbfβ,runx,ppi,transcription factor inhibitor,leukemia,triple negative breast cancer


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