Franklin

Development and characterization of tool compounds targeting the Runt domain's interaction with CBFB / Zaw Min Oo.

Author/Creator:
Oo, Zaw Min, author.
Format/Description:
Thesis/Dissertation
Book
xi, 137 leaves : illustrations (some color) ; 29 cm
Production:
[Philadelphia, Pennsylvania] : University of Pennsylvania, 2015.
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Local subjects:
Penn dissertations -- Cell and molecular biology. (search)
Cell and molecular biology -- Penn dissertations. (search)
Summary:
RUNX1 and CBFB, which encode subunits of the core binding factor, are frequent targets of chromosomal aberrations in hematological malignancies. We previously determined that CBFB (encoded by CBFB) is important for the transforming activity of the chimeric protein AML1-ETO protein (RUNX1-RUNX1T1) generated by the t(8;21), and other studies showed that normal Runx1 functions are essential for survival and maintenance of some leukemias lacking RUNX1 or CBFB mutations. Thus, we hypothesized that we could achieve therapeutic efficacy in multiple leukemias by targeting the Runx1:CBFB interaction with small molecules. Using the structural information of the DNA binding Runt domain (RD) of Runx1 and its interface with CBFB, we employed a computational screen for a library of 78,000 drug-like compounds, and further optimized our leads. The Runt domain inhibitors (RDIs) bind directly to the RD and disrupt its interaction with CBFB. We showed that the RDIs reduced growth and induced apoptosis of t(8;21) acute myeloid leukemia (AML) cell lines, and reduced the progenitor activity of mouse and human leukemia cells harboring the t(8;21), but not normal bone marrow cells. The RDIs had similar effects on murine and human T cell acute lymphocytic leukemia (T-ALL) cell lines that did not harbor the t(8;21). Furthermore, our inclusion of a structurally related and weakly active compound as a control strongly support that the efficacies we observed were due to on target inhibition of RUNX functions. Our results confirmed that the RDIs might prove efficacious in various AMLs, and that a therapeutic window is available to specifically target malignant cells. We developed a pro-drug AI-9-59 with improved solubility and pharmacokinetic properties and assessed whether it has any in vivo efficacies in mouse leukemia models. Our results showed that the pro-drug was toxic to mice at dosage above 50 mg/kg and had no observable growth inhibitory effect on leukemia cells, suggesting that the concentration of the pro-drug necessary to inhibit endogenous core binding factor activity exceeds the maximum tolerated dose in mice. However, the expansion of granulocyte macrophage progenitors, and the gastrointestinal toxicity phenotype we observed suggested that the effects could be from on-target repression of RUNX proteins functions.
Notes:
Ph. D. University of Pennsylvania 2015.
Department: Cell and Molecular Biology.
Supervisor: Nancy A. Speck.
In title and summary, the beta symbol appears after "CBF"
Includes bibliographical references.
Contributor:
Speck, Nancy A., degree supervisor.
Simon, Celeste M., degree committee member.
Hua, Xianxin, degree committee member.
Pear, Warren, degree committee member.
Tong, Wei, degree committee member.
University of Pennsylvania. Department of Cell and Molecular Biology.
ISBN:
9781339427973
OCLC:
946217334