DESIGN OF A POTENT PEPTIDE INHIBITOR OF THE EPIDERMAL GROWTH-FACTOR RECEPTOR TYROSINE KINASE UTILIZING SEQUENCES BASED ON THE NATURAL PHOSPHORYLATION SITES OF PHOSPHOLIPASE C-GAMMA-1

Peptides that possess primary sequences identical to segments surrounding the natural phosphorylation sites of phospholipase C-gamma 1 (i.e., tyrosines 472, 771, 783, and 1284) have been synthesized and evaluated with respect to substrate kinetics for the epidermal growth factor receptor tyrosine kinase. A peptide that was based on tyrosine 472 was the superior substrate in terms of lowest K-m value at 37 mu M and had the following amino acid sequence: Lys-His-Lys-Lys-Leu-Ala-Glu-Gly-Ser-Ala-Tyr(472)-Glu-Glu-Val. This peptide sequence was used as a foundation to make amino acid substitutions and/or chemical modifications directed toward the synthesis of a potent peptide inhibitor. As a result, a nine amino acid peptide was synthesized having a K-i of 10 mu M.