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 sc reening a secondary random peptide library (Q. Lou et at, Bioorg. Med. Chem,, 4: 677-682, 1996). Based on the primary structure of GIYWHHY, we designed and synthesized several pseudosubstrate-based peptide inhi bitors, Some of these peptide inhibitors are highly potent and specifi c with IC50 in the low micromolar range, Because both YIYGSFK and GIYW HHY are efficient and specific substrates for p60(c-src) PTK, chimeric branched peptides based on these two sequences were synthesized. Thes e branched peptides inhibit p60(c-src) PTK with high potency, indicati ng that the enzyme-active site of p60(c-src) PTK can accommodate more than a linear motif, This may explain why seemingly several peptides w ith very different linear structures can all be phosphorylated by this enzyme.