The goal of this project is to develop inhibitors of human sphingosine kinase (SK) that are effective as anticancer therapeutic agents. We have focused on SK as an innovative molecular target for cancer therapy because of its critical role in sphingolipid metabolism, which is known to regulate tumor cell proliferation and apoptosis, as well as angiogenesis. SK produces sphingosine-1-phosphate, which promotes proliferation, and concurrently depletes ceramide, thereby inhibiting apoptosis. Importantly, studies have demonstrated that SK can act as an oncogene, and that SK activity is crucial for Ras-mediated cell proliferation. Additionally, sphingolipid metabolism has been shown to be involved in resistance to many anticancer drugs. Furthermore, we have recently demonstrated that SK is frequently overexpressed in a variety of human tumors, and that SK inhibitors have antitumor activity in vivo. Because of the pivotal role of SK in regulating tumor growth and drug-sensitivity, we propose to optimize SK inhibitors to be used as anticancer drugs. In Preliminary Studies, we have identified novel compounds with SK inhibitory activity, both in vitro and in intact cells, and have developed efficient methods for the synthesis of analogs of these agents. These compounds are more potent than any other known SK inhibitor, and are cytotoxic toward tumor cells, including cell lines with the multidrug resistance phenotype. Furthermore, examples of these compounds have been shown to be orally bioavailable, and to have in vivo antitumor activity in the absence of toxicity to mice. In this project, we will conduct studies that address the following Specific Aims: 1. To optimize the SK inhibitory activity of these compounds. 2. To evaluate the effects of the SK inhibitors on endothelial and cancer cells. 3. To evaluate the anticancer efficacy of the SK inhibitors in vivo. The compounds synthesized and characterized in this project will provide important new pharmacological probes to determine the roles of SK in biological processes, as well as provide lead compounds that can be developed into new anticancer drugs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122226-04
Application #
7758834
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Lees, Robert G
Project Start
2007-04-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
4
Fiscal Year
2010
Total Cost
$277,400
Indirect Cost
Name
Medical University of South Carolina
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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