Targeting Oncogenic Mirnas With Small Molecules For Breast Cancer Therapy

<p><strong>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 <em>in vitro </em>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. </strong></p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2015

Author dc:creator

• Monroig, Paloma del C.

Contributors dc:contributor

• George A. Calin, MD/PhD
• Zahid Siddik, PhD
• Shuxing Zhang, PhD

• cancer
• miRNAs
• breast cancer
• therapeutics
• small molecules
• Medical Biotechnology
• Medical Molecular Biology
• Medicine and Health Sciences
• Nucleic Acids, Nucleotides, and Nucleosides
• Other Chemicals and Drugs

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/609

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1683