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Novel Inhibitors of Sphingosine Kinase

Award Information

Agency:
Department of Health and Human Services
Branch:
N/A
Award ID:
65481
Program Year/Program:
2003 / SBIR
Agency Tracking Number:
CA097833
Solicitation Year:
N/A
Solicitation Topic Code:
N/A
Solicitation Number:
N/A
Small Business Information
APOGEE BIOTECHNOLOGY CORPORATION
1214 Research Blvd Suite 2014 HUMMELSTOWN, PA 17036-9196
View profile »
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
 
Phase 1
Fiscal Year: 2003
Title: Novel Inhibitors of Sphingosine Kinase
Agency: HHS
Contract: 1R43CA097833-01A2
Award Amount: $473,108.00
 

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.

Principal Investigator:

Kevin J. French
7175668635
KJFRENCH@APOGEE-BIOTECH.COM

Business Contact:

Charles Smith
7175209674
CDSMITH@APOGEEBIOTECH.COM
Small Business Information at Submission:

APOGEE BIOTECHNOLOGY CORPORATION
PO BOX 916 HERSHEY, PA 17033

EIN/Tax ID: 251901043
DUNS: N/A
Number of Employees: N/A
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No