Development of Hif-1Α/Hif-1Β Heterodimerization Inhibitors Using A Novel Bioluminescence Reporter Assay System For In Vitro High Throughput Screening and In Vivo Imaging

<p>Tumor growth often outpaces its vascularization, leading to development of a hypoxic tumor microenvironment. In response, an intracellular hypoxia survival pathway is initiated by heterodimerization of hypoxia-inducible factor (HIF)-1α and HIF-1β, which subsequently upregulates the expression of several hypoxia-inducible genes, promotes cell survival and stimulates angiogenesis in the oxygen-deprived environment. Hypoxic tumor regions are often associated with resistance to various classes of radio- or chemotherapeutic agents. Therefore, development of HIF-1α/β heterodimerization inhibitors may provide a novel approach to anti-cancer therapy. To this end, a novel approach for imaging HIF-1α/β heterodimerization <em>in vitro </em>and<em> in vivo </em>was developed in this study<em>.</em> Using this screening platform, we identified a promising lead candidate and further chemically derivatized the lead candidate to assess the structure-activity relationship (SAR). The most effective first generation drug inhibitors were selected and their pharmacodynamics and anti-tumor efficacy <em>in vivo</em> were verified by bioluminescence imaging (BLI) of HIF-1α/β heterodimerization in the xenograft tumor model. Furthermore, the first generation drug inhibitors, M-TMCP and D-TMCP, demonstrated efficacy as monotherapies, resulting in tumor growth inhibition via disruption of HIF-1 signaling-mediated tumor stromal neoangiogenesis.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2013

Author dc:creator

• Chiang, Yun-Chen

Contributors dc:contributor

• Juri Gelovani, M.D., Ph.D.
• Victor Krasnykh, Ph.D.
• Edward F. Jackson, Ph.D.

• HIF-1α/β heterodimerization
• HIF-1α inhibitor
• cancer therapy
• molecular imaging
• high-content screnning
• split luciferase complementation assay
• Medical Biotechnology
• Medical Molecular Biology
• Medicine and Health Sciences
• Pharmaceutics and Drug Design
• Therapeutics

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/383

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1426