Myocardial and cerebral infarctions, conditions which are primarily the result of atherosclerotic lesions within the coronary and cerebral blood vessels, are the leading causes of death in Western civilization. A causal link between hypercholesterolemia and the premature development of atherosclerosis is well established. Hepatic biosynthesis is responsible for the majority of cholesterol transported in plasma lipoproteins. The rate-limiting enzyme of cholesterol biosynthesis, HMG CoA reductase, is therefore a prime target for drug intervention. Liver cells contain a protein kinase capable of almost totally inactivating HMG CoA reductase. This kinase is regulated allosterically by 5'-AMP and protein phosphorylation via a second kinase. The ultimate objective of this project is to discover novel, cell-permeable activators of the AMP-activated kinase as potential anti- hypercholesterolemic agents. In Phase I, substrates, assays and a purification scheme for the AMP-activated protein kinase were developed. Furthermore, a novel activator of this kinase was discovered in an initial screen of Oncogene Science's chemical file. Phase II of the project will include cloning and expression of the human AMP-kinase, development of a high-throughput kinase assay, and development of secondary cellular screens to determine the effects of activators of the AMP-kinase on intact cells and on HMG CoA reductase activity in vivo.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
5R44HL044829-03
Application #
3508783
Study Section
Special Emphasis Panel (SSS (B2))
Project Start
1990-05-01
Project End
1994-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Osi Pharmaceuticals, Inc.
Department
Type
DUNS #
City
Uniondale
State
NY
Country
United States
Zip Code
11553