The specific aims of this proposal are to explore potential new protein kinase inhibitor designs, some of which may be broadly applied and others of which may have enhanced selectivity for individual kinases. The new inhibitor designs will be tested against three growth factor receptor tyrosine kinases, eight oncogene-related tyrosine kinases, three isozymes of protein kinase C, and cAMP-dependent protein kinase. This research could lead to inhibitors which would be useful for investigating the biological significance of individual protein kinases and ultimately for various therapeutic applications. The most promising potential therapeutic uses may be in the anti-cancer and anti-AIDS areas for isozyme-selective protein kinase C inhibitors and in the anti-cancer and immunomodulator areas for tyrosine kinase inhibitors. Other potential therapeutic applications include myosin light chain kinase inhibitors as anti- hypertensive agents. Our long term objectives are to utilize our most successful inhibitor designs to prepare prototype anti-cancer, anti-AIDS, immunosuppressant and anti-hypertensive protein kinase inhibitors which may be used as lead compounds for a more extensive research program aimed at developing clinically useful drugs. This proposal is focused upon four structural classes of inhibitor designs which are appended to small peptides and may extend into the catalytic region of the kinase active sites, yet bind non-competitively with ATP or ADP. The appendages are intended to enhance binding by interacting with the catalytic residues, Mg2+ ATP or Mg2+ ADP. A first level of inhibitor selectivity will be achieved by choosing the peptide sequence based upon the substrate selectivity for the individual kinase(s). A second level of selectivity will be sought by widely testing the inhibitor designs in anticipation of differing abilities of the individual kinases to accommodate the unnatural appendages. This anticipation is precedented by literature reports showing selectivities on the order of 10-5,000 fold among isozymes of particular enzymes with substrate-derived inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA052800-03
Application #
2094995
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1991-07-01
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1995-06-30
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260