Optimization of the Activity and Metabolism of Amidine-based Sphingosine Kinase Inhibitors

Houck, Joseph Daniel, Department of Chemistry, University of Virginia
McGarvey, Glenn, Department of Chemistry, University of Virginia
Mandell, James, Department of Pathology, University of Virginia
Macdonald, Timothy, Department of Chemistry, University of Virginia

Today, cancer is treated with toxic chemicals, known as chemotherapies that have limited success treating one of the biggest killers in the United States and have significant side effects. Soon there may be a treatment with fewer side effects: targeted anti-cancer agents are directed at a specific cellular disorder underlying the disease. The research described herein aims to elucidate the role of the sphingosine kinases (SphKs) as a driving force in cancer progression. The SphKs control the production of the potent signaling molecule sphingosine 1-phosphate (S1P), responsible for cell growth, survival and migration. The SphKs are the sole producer of S1P, and inhibitors of the SphKs may prove useful as cancer therapies. SphK1 has been intensely studied, with over-expression observed in a variety of tumor cell lines. This isoform is presumed to be the target of interest over the less characterized SphK2. A series of potent, amidine-based SphK inhibitors has proven their effectiveness at inhibiting SphK1 and reducing cellular S1P concentrations in numerous cell lines and in whole animals. Inhibitors of this type have the potential to serve as targeted cancer therapeutics and will serve as tools to investigate the unknown relationship between the two kinase isoforms. To date, the Macdonald laboratory has developed some of the most potent and selective SphK1 inhibitors found in the chemical literature. One pitfall of these amidinebased inhibitors is their short half-life in the body. A strategy to circumvent the issue of a drug's short half-life is to replace unstable functional groups with more stable groups that will not be metabolized by enzymes in the body. A library of five-membered heterocycles as amide-bond isosteres has proved to be equipotent to amide counterparts and have an increased biological half-life. iiOptimization of this scaffold through structure-activity relationship studies and rational design with a SphK1 homology model has led to inhibitors with nanomolar potencies. This family of heterocyclic inhibitors was evaluated in human leukemia U937 cells to assess their ability to lower S1P levels. More potent, longer-lived compounds will provide scientists with tools to investigate the role of the sphingosine kinases in cancer and other disease states. iiiTo Mom and Dad, for their constant love and encouragement and To Emma, for her companionship Contents ivAbstract…………………………………………………………………………………....

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PHD (Doctor of Philosophy)
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