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Pharmacological Targeting of Sphingosine Kinase: Conventional, Bisubstrate, and Irreversible Inhibitors

Dawson, Thomas
Thesis/Dissertation; Online
Dawson, Thomas
Macdonald, Timothy
Cancer is rapidly becoming the world’s greatest health problem, and current treatments are often harsh and ineffective. The demand for improved modes of therapy has fueled research in recent decades and led to a deeper, more fundamental understanding of cancer biology. Today, drug discoverers exploit knowledge of tumor growth and stress-support pathways to develop therapeutics with novel mechanisms of action, greater selectivity for cancer cells, lower toxicity, and, theoretically, greater efficacy. A particularly attractive target for new cancer drugs is the sphingolipid signaling pathway. Cellular levels of the lipids ceramide, sphingosine, and sphingosine 1-phosphate (S1P) are strictly regulated by various enzymes, and play a large role in determining cellular growth and fate. Specifically, S1P has emerged as a driver of processes such as cell growth, proliferation, inflammation, resistance to apoptosis, and angiogenesis, and has been implicated in nearly every type of cancer. Thus, biomolecular agents that affect levels of S1P may be viable as targeted cancer therapies or for the treatment of hyperproliferative and inflammatory diseases. As the sole producers of physiological S1P, the two sphingosine kinases (SphK1 and SphK2) have been the subject of intense investigation during the last decade. Many inhibitors of the SphKs have been discovered, and have proven to be effective pharmacological probes of these kinases. However, significant improvements in the potency, SphK-subtype selectivity, and pharmacokinetic properties of SphK inhibitors remain necessary to fully elucidate the roles of SphK1 and SphK2 in the context of cancer and other diseases, and to maximize the therapeutic potential of these molecules. To this end, our efforts of the last several years have centered on the development of SphK inhibitors. The work described herein represents the culmination of one phase of our SphK inhibition project, and the early stages of another. In Chapter 3, the design, evaluation, and in silico analysis of a unique class of amidine-containing SphK1 inhibitors is detailed. This study revealed key structural requirements for inhibition of SphK1 and resulted in the identification of the most selective SphK1 inhibitor reported to date. Next, in Chapter 4, efforts to target SphK2 are described that employed a conventional, substrate-based approach. In this work, one of the most active substrates of SphK2 was identified, and a small library of related inhibitors was generated. Finally, Chapter 5 describes two novel methods of targeting SphK2: bisubstrate and irreversible inhibition. The pharmacological justification, design, synthesis, and evaluation of these molecules are presented in detail.
University of Virginia, Department of Chemistry, PhD, 2016
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