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Potent Pseudosubstrate-based Peptide Inhibitors for p60^c-src Protein Tyrosine Kinase¹

Department of Medicine, Arizona Cancer Center [Q. L., M. E. L., R. T. M., S. E. S., L. R., K. S. L.] and Department of Microbiology and Immunology [K. S. L.], University of Arizona College of Medicine, Tucson, Arizona 85724

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 GIYWHHY are efficient and specific substrates for p60^c-arc 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-arc 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.

¹ This work was supported by NIH Grants CA17094, CA57723, and CA23074, and National Science Foundation Grant (MCB-9506217). K. S. L. is a Scholar of the Leukemia Society of America.

² To whom requests for reprints should be addressed, at Arizona Cancer Center, University of Arizona, 1515 North Campbell Avenue, Tucson, AZ 85724. Phone: (520) 626-2333; Fax: (520) 626-2284; E-mail: klam@azcc.arizona.edu.

Received 9/16/96. Accepted 3/17/97.

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