Cyclic peptides incorporating 4-carboxyphenylalanine and phosphotyrosine are potent inhibitors of pp60(c-src)

The protein tyrosine kinase, pp60c-src, is involved in cellular signaling and is activated during mitosis and in various tumors. We have been employing cyclic decapeptides to identify the determinants for substrate binding and phosphorylation to develop inhibitors competitive with protein substrates of Src. A structure−activity study [McMurray, J. S., Budde, R. J. A., Ke, S., Obeyesekere, O. U., Wang, W., Ramdas, L., and Lewis, C. A. (1998) Arch. Biochem. Biophys. 355, 124] revealed that, at the position 3 residues C-terminal to the phosphorylated tyrosine (Y + 3), both glutamic acid and phenylalanine gave identical Ki, Km, and Vmax values. We hypothesized that the area of Src that binds the Y + 3 residue contains either a positively charged lysine or an arginine, capable of ionic interactions with glutamic acid or cation−π interactions with phenylalanine. To test this hypothesis, a series of phenylalanine analogues were substituted at position 7 (the Y + 3 residue) in cyclo(Asp1−Asn2−Glu3−Tyr4−Ala5−Phe6−...