Potent pseudosubstrate-based peptide inhibitors for p60(c-src) protein tyrosine kinase

We recently reported the identification of GIYWHHY as an efficient and specific substrate for p60(c-src) protein tyrosine kinase (PTK) by screening a secondary random peptide library (Q. Lou et al., Bioorg. Med. Chem., 4: 677-682, 1996). Based on the primary structure of GIYWHHY, we designed and synthesized several pseudosubstrate-based peptide inhibitors. Some of these peptide inhibitors are highly potent and specific with IC₅₀ in the low micromolar range. Because both YIYGSFK and GIY-WHHY are efficient and specific substrates for p60(c-src) PTK, chimeric branched peptides based on these two sequences were synthesized. These branched peptides inhibit p60(c- src) PTK with high potency, indicating that the enzyme-active site of p60(c- src) PTK can accommodate more than a linear motif. This may explain why seemingly several peptides with very different linear structures can all be phosphorylated by this enzyme.