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Abstract
Grant Number: 1R43CA097833-01A2 PI Name: FRENCH, KEVIN J. PI Email: kfrench@apogeebiotech.com PI Title: Project Title: Novel Inhibitors of Sphingosine Kinase Abstract: DESCRIPTION (provided by applicant): The long-term goal of this program is to identify and evaluate novel inhibitors of human sphingosine kinase (SK) as anticancer therapeutic agents. We have focused on SK as a innovative molecular target for cancer therapy because of its critical role in sphingolipid metabolism, which is known to regulate cell proliferation and apoptosis. SK produces sphingosine-1-phosphate which promotes mitogenesis and concurrently depletes ceramide, thereby inhibiting apoptosis. Importantly, recent studies have demonstrated that SK can act as an oncogene. Overexpression of SK in NIH/3T3 cells results in cellular transformation and allows these cells to grow as tumors. Additionally, SK activity has been found to be crucial for Ras-mediated cell proliferation. Furthermore, we demonstrate herein that SK is frequently overexpressed in a variety of human tumors. In spite of this accumulating evidence for a pivotal role of SK in regulating tumor growth, pharmacological inhibition of SK is an untested means of treating cancer. This is due to the current lack of specific SK inhibitors. To overcome this problem, we have initiated a project to identify and evaluate such inhibitors of SK. By screening libraries of synthetic compounds, we have identified novel inhibitors of recombinant human SK. These compounds are more potent than any other known SK inhibitor, and do not compete for the ATP binding site of the enzyme. The SK inhibitors are cytotoxic toward tumor cells, including cell lines with the multidrug resistance phenotype. To provide proof-of-principle evaluations of the potential utility of these compounds, the following Specific Aims will be addressed in Phase I of this project: 1) To evaluate the specificities of SK inhibitors using in vitro and cellular assays; 2) To optimize the SK inhibitory activity of selected chemotypes; and 3) To evaluate the in vivo toxicity, pharmacokinetics and antitumor activity of SK inhibitors.
Thesaurus Terms:
alcohol phosphotransferase, antineoplastic, drug screening /evaluation, enzyme inhibitor, sphingosine
combinatorial chemistry, cytotoxicity, drug discovery /isolation, pharmacokinetics
SCID mouse, cell line, flow cytometry, mass spectrometry, nuclear magnetic resonance spectroscopy, terminal nick end labeling
Institution: APOGEE BIOTECHNOLOGY CORPORATION 245 CANDLEWYCK LN HERSHEY, PA 17033 Fiscal Year: 2003 Department: Project Start: 29-JUL-2003 Project End: 30-JUN-2005 ICD: NATIONAL CANCER INSTITUTE IRG: ZCA1
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