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
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