Date of Graduation

12-2015

Document Type

Dissertation (PhD)

Program Affiliation

Experimental Therapeutics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

George A. Calin, MD/PhD

Committee Member

Zahid Siddik, PhD

Committee Member

Shuxing Zhang, PhD

Committee Member

Dianna Milewicz, MD/PhD

Committee Member

Geoffrey Bartholomeusz, PhD

Abstract

The crucial role of microRNAs (miRNAs) in cancer pathobiology has driven the introduction of new drug development approaches such as miRNA inhibition. In order to advance miRNA-therapeutics, there is a need to develop screening strategies that can target tumors in a specific way. Small molecule inhibitors represent an attractive approach to pursue this. However, the absence of molecular structures for most of the miRNAs makes it very difficult to predict which inhibitors can bind to them. Herein we designed a strategy to screen for small molecules by assesing whether they could directly bind/ interact with miR-10b/miR-21. As part of our results, we found a new mechanism of action for the multi-tyrosine kinase inhibitor Linifanib (5-6A); it inhibits miR-10b in vitro in breast cancer (BC) models. Furthermore, we confirmed that Linifanib (5-6A) interacts with the precursor sequence of miR-10b through nuclear magnetic resonance (NMR). Overall, our findings demonstrate an effective strategy to screen for small molecule inhibitors of miRNAs (SMIRs), one that is applicable for any disease type in which miRNA overexpression promotes pathology. More so, we provide a first-in-class lead compound for further development in cancer therapeutics.

Keywords

cancer, miRNAs, breast cancer, therapeutics, small molecules

Available for download on Saturday, December 17, 2016

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