Abstract |
The cytoplasmic protein p60c-src, an ubiquitous non- receptor protein tyrosine kinase (PTK) is a potential anticancer target as it is over-expressed and/or constitutively active in several cancer types. In addition, the phenotype of c-src knock-out mice is consistent with osteopetrosis, which suggests that inhibitors against this enzyme may also be therapeutic for osteoporosis. Using a known peptide substrate for c-src, MIYKYYF, as a template, we have developed a series of pseudosubstrate-based peptide inhibitors. Structure-activity relationship studies have been performed on one of these inhibitors, CIYKYYF. In a kinase assay using YIYGSFK as the substrate, CIYKYY has been demonstrated to inhibit p60c-src, with an IC50 of 0.6 microm. Further truncation has led to the determination that even the smaller peptide, CIYK, is a moderately potent inhibitor with IC50 of 15 microm. Some improvement in inhibitory potency (IC50 = 11.8 microm) has been observed with the replacement of Tyr3 in CIYK with beta- phenylalanine (beta-Phe). The tetrapeptide CI(beta-Phe)K will be used as a lead compound for future development of peptidomimetics and small molecule inhibitors that have the capacity to penetrate the plasma membrane of intact cells.
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Authors | J R Kamath, R Liu, A M Enstrom, Q Lou, K S Lam |
Journal | The journal of peptide research : official journal of the American Peptide Society
(J Pept Res)
Vol. 62
Issue 6
Pg. 260-8
(Dec 2003)
ISSN: 1397-002X [Print] Denmark |
PMID | 14632929
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Enzyme Inhibitors
- Peptide Fragments
- Peptides
- Proto-Oncogene Proteins pp60(c-src)
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Topics |
- Amino Acid Sequence
- Drug Design
- Enzyme Inhibitors
(chemical synthesis, chemistry, pharmacology)
- Humans
- Inhibitory Concentration 50
- Molecular Sequence Data
- Molecular Structure
- Peptide Fragments
(chemistry, metabolism)
- Peptides
(chemistry, metabolism)
- Proto-Oncogene Proteins pp60(c-src)
(antagonists & inhibitors, metabolism)
- Structure-Activity Relationship
- Substrate Specificity
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