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Specific Inhibitors of Tyrosine-specific Protein Kinases: Properties of 4-Hydroxycinnamamide Derivatives in Vitro

Departments of Oncogene Research [T. S., M. T., T. K.] and Tumor Virology [M. K. O.], Research Institute for Microbial Diseases, Osaka University, Osaka 565, Japan, and Biochemical Research Laboratories, Kanegafuchi Chemical Industry Co., Ltd., Takasago, Hyogo 676, Japan [T. S., T. Y., K. W.]

Inhibition by seven synthetic 4-hydroxycinnamamide derivatives, ST 271, ST 280, ST 458, ST 494, ST 633, ST 638, and ST 642, of tyrosine-specific protein kinases (tyrosine kinase) of oncogene or proto-oncogene products (p130gag-v-fps, p70gag-actin-v-fgr, pp60v-src, pp60c-src) and epidermal growth factor (EGF) receptor kinase were investigated. ST 638 (-cyano-3-ethoxy-4-hydroxy-5-phenylthiomethylcinnamamide) strongly inhibited more of the tyrosine kinases than any of the other compounds. The susceptibilities of these tyrosine kinases to ST 638 increased in the following order: EGF receptor > p70gag-actin-v-fgr > pp60c-src > p130gag-v-fps, pp60v-src, with 50% inhibitory concentration values of 1.1, 4.2, 18, 70, and 87 µM, respectively. The phosphorylation of the tyrosine residues in particulate fractions from RR1022 cells expressing pp60v-src was inhibited by ST 638 in a dose-dependent way, while it had a negligible effect on the phosphorylations of threonine and serine residues. Kinetic analysis showed that ST 638 competitively inhibited the phosphorylation of an exogenous substrate by the EGF receptor kinase with a K_i of 2.1 µM. ST 638 noncompetitively inhibited autophosphorylation by EGF receptor kinase. These results indicate that ST 638 is a potent and specific inhibitor of tyrosine kinases in vitro, and that its inhibitory activity is caused by competing with the substrate protein for the tyrosine kinase binding site.

¹ To whom reprint requests should be addressed.

² Supported by a Grant-in-Aid for a special project on Cancer-Bioscience (No. 63614518) from the Ministry of Education, Science and Culture of Japan. Deceased September 21, 1988.

³ Present address: Department of Molecular Bioregulation, Institute of Molecular and Cellular Biology for Pharmaceutical University, Yamashina, Kyoto 607, Japan.

Received 9/ 6/88. Revised 1/ 6/89. Accepted 1/26/89.

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