Oncogenes and Mitotic Division, Kinetochores and Anaphase, Lung Cancer, Nuclear Magnetic Resonance (NMR), Drug-Design, Animal Models.
Using Nuclear Magnetic Resonance for Drug-Design and to characterize oncogenes.
University of Colorado Anschutz Medical Campus, Dept. of Biochemistry and Molecular Genetics
To determine at atomic level how Spindly protein, which is a motor adaptor in the cell, binds to the kinetochore prior to anaphase. We also aim to design small molecules that target Spindly and serve as potential antitumor agents in lung cancer.
Spindly protein is a motor adaptor that mediates the binding between the kinetochore and the dynein machinery. At the onset of anaphase, Spindly which is bound to the dynein motor machinery strips away the spindle assembly checkpoint proteins towards the minus end of the microtubule thereby allowing the cell to enter the anaphase.
Spindly is known as a potential target for drug-discovery targeting cancer. It was found that silencing Spindly in combination with Paclitaxel delays the mitotic exit and potentiates the action of Paclitaxel in lung cancer cell lines.
Therefore, it is our goal to study the C-terminal tail of Spindly to provide molecular insight at atomic resolution into how it engages with functionally diverse kinetochore components and to design Spindly inhibitors as potential antitumor agents. We apply NMR and other biophysical techniques to study the interactions and dynamics of the protein. In addition, we will pursue a Fragment-Based Drug Design approach using NMR, through which we will test different small compounds for binding Spindly and their effect on complex formation between Spindly and the kinetochore. We also collaborate with a group in Portugal (R. Gassmann) to verify our results using CRISPR-Cas9 in C. elegans.
We expect that our results will report for the first time on the structure of the pharmacophore essential for binding Spindly in addition to designing high affinity lead compounds.