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Assessment of functional characteristics of small GTPases using small molecules


Please use this identifier to cite or link to this item: http://hdl.handle.net/1928/17461

Assessment of functional characteristics of small GTPases using small molecules

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dc.contributor.author Agola, Jacob
dc.date.accessioned 2012-02-01T17:45:35Z
dc.date.available 2012-02-01T17:45:35Z
dc.date.issued 2012-02-01
dc.date.submitted December 2011
dc.identifier.uri http://hdl.handle.net/1928/17461
dc.description.abstract Rab and Rho subfamilies of GTPases are functionally linked to intracellular trafficking and organization of the cytoskeleton respectively. Despite their roles, use of small molecule inhibitors or activators to map the functionality of these GTPases remains largely underexplored due to lack of suitable compounds. In this dissertation, we report on the functional characterization of Rab7 and Rac1 GTPases using small molecules. 2-(benzoylcarbamothioylamino)-5,5-dimethyl-4,7- dihydrothieno[2,3-c]pyran-3-carboxylic acid (PubChem #: CID1067700) has been used to characterize Rab7. Using bead based flow cytometry, CID1067700 was found to have significant inhibitory potency on Rab7 nucleotide binding with a respective inhibitory efficacy of 80% for BODIPY-GTP and 60% for BODIPY-GDP binding. Rac1 has been functionally characterized by non-steroidal anti-inflammatory drug (NSAID), R-Naproxen in the context of ovarian cancer. R-Naproxen isoform functionally inhibited Rac1 in the cell lines assayed relative to S-Naproxen and structurally similar 6-methoxy-2-naphthylacetic Acid (6-MNA). Inhibition is based on interference with membrane distribution of Rac1 rather than overall protein levels. Taken together, this study has identified the first competitive GTPase inhibitor (CID1067700) and also demonstrated the potential utility of the compound for dissecting GTPase enzymology. The study has also shown that R-Naproxen blocks activation of Rac1 small GTPase in ovarian cancer cells with implications for the inhibition of ovarian cancer cell proliferation, migration, and invasion. en_US
dc.description.sponsorship University of New Mexico (UNM), National Science Foundation (NSF) and National Institutes of Health (NIH) en_US
dc.language.iso en_US en_US
dc.subject Rab, Rho, Rac, Cdc42 and Ras GTPases; drug discovery; fluorescent GTP and GDP; enzyme kinetics; GEF; flow cytometry, ovarian cancer, competitive and allosteric inhibitors en_US
dc.subject.lcsh Guanosine triphosphatase.
dc.subject.lcsh Nonsteroidal anti-inflammatory agents.
dc.subject.lcsh Enzyme kinetics.
dc.title Assessment of functional characteristics of small GTPases using small molecules en_US
dc.type Dissertation en_US
dc.description.degree Biomedical Sciences en_US
dc.description.level Doctoral en_US
dc.description.department University of New Mexico. Biomedical Sciences Graduate Program en_US
dc.description.advisor Wandinger-Ness, Angela
dc.description.committee-member Hudson, Laurie
dc.description.committee-member Prossnitz, Eric
dc.description.committee-member Buranda, Tione
dc.description.committee-member Sklar, Larry

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