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 μM. Further truncation has led to the determination that even the smaller peptide, CIYK, is a moderately potent inhibitor with IC50 of 15 μM. Some improvement in inhibitory potency (IC 50 = 11.8 μM) has been observed with the replacement of Tyr 3 in CIYK with β-phenylalanine (β-Phe). The tetrapeptide CI(β-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.
- p60 protein tyrosine kinase
- Protein kinase assay with thin layer chromatography
- Pseudosubstrate-based peptide inhibitors
- Structure-activity relationship study
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