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Po-Ting Lai - dissertation.pdf (46.92 MB)

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DEVELOPMENT OF SMALL MOLECULES BLOCKING GLUCOSE TRANSPORTER OR INHIBITING HSP90 FOR THE THERAPY OF CANCER

Lai, Po-Ting
http://rave.ohiolink.edu/etdc/view?acc_num=osu1480442501818014

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
Cancer has become a leading cause of death worldwide. With increased understanding of the mechanisms of cancer cell survival and progression, targeted cancer therapy has become a major approach for development of future cancer therapies. Here in this dissertation, we would like to present two approaches to develop next generation cancer drugs: the first is glucose transporter (GLUT) inhibitors and the second is HSP90 inhibitors. Cancer cells undergo metabolic reprogramming, called the Warburg effect, characterized by a shift to aerobic glycolysis. This metabolic difference between malignant cells and normal cells provides a therapeutic opportunity to inhibit cancer cell growth without harming normal cells. Previously in our lab, we identified a novel thiazolidinedione derivative, OSU-CG5, as a potent GLUT inhibitor to inhibit cancer cell proliferation. However, the in vivo efficacy of this compound did not correlate with the profound in vitro activity. In this study, we constructed a library of OSU-CG5 derivatives to search for more potent agents. CG-77 has been identified as the next generation GLUT inhibitor with the replacement of the phenol group with a sulfonamide group. This modification not only improved the in vitro activity in several cancer cell lines, but also the in vivo efficacy as demonstrated in a PC3 xenograft mouse model. Furthermore, we have shown that CG-77 is capable of inhibiting aberrant Wnt signaling pathway in colon cancer cells. Specifically, CG-77 inhibits the formation of ß-catenin/TCF4 complexes and thus inhibits the expression of oncogenic Wnt target proteins. These findings demonstrate the involvement of GLUT1 in the Wnt signaling pathway and provides a rationale for investigating its potential use for colorectal cancer therapy. The HSP90 chaperone is a key component in the protein maturation and stabilization process. There is a long history of the development of HSP90 inhibitors; however, none have been approved by the FDA so far. In this study, we have identified doxazosin and its derivative DZ-301 as potent HSP90 inhibitors to inhibit cancer cell growth. This is the first report of molecules with the quinazoline scaffold acting as HSP90 inhibitors. We demonstrated the HSP90 inhibitory activity of doxazosin and DZ-301 by using Western blot analysis, RT-PCR analysis, and protein pull-down assay. Further research indicated that DZ-301 inhibited cancer cell growth through apoptosis. The in vivo efficacy of DZ- 301 is currently being investigated in a PC3 xenograft model. We will also use computational modeling to further develop these novel quinazoline-based HSP90 inhibitors.
Ching-Shih Chen (Advisor)
James R. Fuchs (Committee Member)
Mark Mitton-Fry (Committee Member)
Karl A. Werbovetz (Committee Member)
133 p.
Biomedical Research; Organic Chemistry; Pharmacy Sciences
glucose transporter inhibitors, HSP90 inhibitors

Recommended Citations

Citations

  • Lai, P.-T. (2016). DEVELOPMENT OF SMALL MOLECULES BLOCKING GLUCOSE TRANSPORTER OR INHIBITING HSP90 FOR THE THERAPY OF CANCER [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1480442501818014

    APA Style (7th edition)

  • Lai, Po-Ting. DEVELOPMENT OF SMALL MOLECULES BLOCKING GLUCOSE TRANSPORTER OR INHIBITING HSP90 FOR THE THERAPY OF CANCER. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1480442501818014.

    MLA Style (8th edition)

  • Lai, Po-Ting. "DEVELOPMENT OF SMALL MOLECULES BLOCKING GLUCOSE TRANSPORTER OR INHIBITING HSP90 FOR THE THERAPY OF CANCER." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1480442501818014

    Chicago Manual of Style (17th edition)

osu1480442501818014
17
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This open access ETD is published by The Ohio State University and OhioLINK.