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Development of Sphingosine Kinase 1 Inhibitors for the Treatment of Cancer Progression

Kennedy, Andrew John
Thesis/Dissertation; Online
Kennedy, Andrew John
Mandell, James
Macdonald, Timothy
McGarvey, Glenn
Harman, Dean
Sphingosine I - phosphate (SIP) is an endogenous lipid responsible for the regulation of cell growth, survival, and migration. In healthy tissue, SIP signaling controls tissue repair, neovascularization, cellular trafficking, and proliferation. Therefore, it is not surprising that SIP has been identified as an accelerant of cancer progression and that the enzymes that control SIP concentration and location have been identified as oncological targets. The sphingosine kinases (SphKs) are the sole producers of SIP and thus SphK inhibitors may prove effective in cancer mitigation and chemosensitization. Of the two SphKs, SphKI overexpression has been observed in a myriad of cancer cell lines and tissues, and has been recognized as the presumptive target over that of the poorly characterized SphK2. The development of potent and subtype - selective small molecular inhibitors of the SphKs is critical for elucidating the complimentary, opposing, or potentially independent roles of the two SphKs in differing diseased states. Presented here is the development of amidine - based sphingosine kinase I (SphKI) inhibitors; including the initial inhibitor design and subsequent amidine lead discovery for SphK inhibition. Several structure activity relationships of the lead amidine - based inhibitor were investigated and were used in the design of more potent SphKI selective inhibitors. This library of SphK inhibitors was then used to aid the generation of SphK homology models that were based on the solved crystal structure for diacylglycerol kinase [5. The SphK homology models and amidines designed to mimic known substrates such as FTY-720 and sphingosine were used to generate a mechanism of amidine inhibition. The homology model of SphKl, trained with this library of amidine inhibitors, was then used to predict the activity of additional, more potent, inhibitors. Lastly, select amidine inhibitors were validated in human leukemia U937 cells, where they significantly reduced endogenous S 1P levels at nanomolar concentrations. The library of SphKl selective inhibitors developed here represents only half of the desired family of tools necessary to examine the functions of SphK 1 and 2 in cancer. However, the SphK homology models developed are the first in their class and will be essential in the future design of SphK2 selective inhibitors. Note: Abstract extracted from PDF file via OCR
University of Virginia, Department of Chemistry, PHD, 2011
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