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Potent and Specific Inhibitors of Protein Kinase C of Microbial Origin

Bio/Technology volume 8, pages 732–735 (1990)Cite this article

Abstract

Potent and specific inhibitors of protein kinase C have been found in streptomyces and fungi: Staurosporine, an alkaloid from Streptomyces sp., is the most potent inhibitor of protein kinases with an IC50 in the nanomolar range. UCN-01 (7-hydroxy staurosporine), isolated from Streptomyces sp., is a selective inhibitor of protein kinase C with antitumor activity. Calphostin, isolated from the fungus Cladosporium cladosporioides, specifically inhibits protein kinase C (IC50 = 0.05 μM) without inhibiting other protein kinases. Microbial metabolites appear to be a promising source of inhibitors that target signal transduction pathways of eukaryotes.

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References

  1. Hunter, T. 1987. A thousand and one protein kinases. Cell 50: 823–829.

    Article  CAS  Google Scholar 

  2. Hanks, S.K., Quinn, A.M. and Hunter, T. 1988. The protein kinase family: conserved features and deduced phylogeny of catalytic domains. Science 241: 42–52.

    Article  CAS  Google Scholar 

  3. Nishizuka, Y. 1986. Studies and perspectives of protein kinase C. Science 233: 305–312.

    Article  CAS  Google Scholar 

  4. Castagna, M., Takai, Y., Kaibuchi, K., Sano, K., Kikkawa, U. and Nishizuka, Y. 1982. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J. Biol. Chem. 257: 7847–7851.

    CAS  Google Scholar 

  5. Nishizuka, Y. 1988. The molecular heterogeneity of protein kinase C and its implication for cellular regulation. Nature 334: 661–665.

    Article  CAS  Google Scholar 

  6. Tamaoki, T., Nomoto, H., Takahashi, I., Kato, Y., Morimoto, M. and Tomita, F. 1986. Staurosporine, a potent inhibitor of phospholipid/Ca2+ dependent protein kinase. Biochem. Biophys. Res. Commun. 135: 397–402.

    Article  CAS  Google Scholar 

  7. Takahashi, I., Kobayashi, E., Asano, K., Yoshida, M. and Nakano, H. 1987. UCN-01, a selective inhibitor of protein kinase C from streptomyces. J. Antibiot. 40: 1782–1784.

    Article  CAS  Google Scholar 

  8. Takahashi, I., Kobayashi, E., Asano, K., Kawamoto, I., Tamaoki, T. and Nakano, H. 1989. UCN-01 and UCN-02, new selective inhibitors of protein kinase C I. Screening, producing organism and fermentation. J. Antibiot. 42: 564–570.

    Article  CAS  Google Scholar 

  9. Kase, H., Iwahashi, K., Nakanishi, S., Matsuda, Y., Yamada, K., Takahashi, M., Murakata, C., Sato, A. and Kaneko, M. 1987. K-252 compounds, novel and potent inhibitors of protein kinase C and cyclic nucleotide-dependent protein kinases. Biochem. Biophys. Res. Commun. 142: 436–440.

    Article  CAS  Google Scholar 

  10. Hidaka, H., Inagaki, M., Kawamoto, S. and Sasaki, Y. 1984. Isoquino-linesulfonamide, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. Biochemistry 23: 5036–5041.

    Article  CAS  Google Scholar 

  11. Hannum, Y.A. and Bell, R.M. 1988. Aminoacridines, potent inhibitors of protein kinase C. J. Biol. Chem. 263: 5124–5131.

    Google Scholar 

  12. Lomis, C.R. and Bell, R.M. 1988. Sangivamycin, a nucleotide analogue, is a potent inhibitor of protein kinase C. J. Biol. Chem. 263: 1682–1692.

    Google Scholar 

  13. Kobayashi, E., Nakano, H., Morimoto, M. and Tamaoki, T. 1989. Calphostin C (UCN1028C), a novel microbial compound, is a highly potent and specific inhibitor of protein kinase C. Biochem. Biophys. Res. Commun. 159: 548–553.

    Article  CAS  Google Scholar 

  14. Kuyama, S. and Tamura, T. 1957. Cercosporin, a pigment of Cercosporina kikuchii. J. Am. Chem. Soc. 79: 5725–5729.

    Article  CAS  Google Scholar 

  15. Mori, T., Takai, Y., Minakuchi, R., Yu, B. and Nishizuka, Y. 1983. Inhibitory action of chlorpromazine, dibucaine and other phospholipid-interacting drugs on protein kinase C. J. Biol. Chem. 255: 8378–8380.

    Google Scholar 

  16. Wise, B.C. and Kuo, J.F. 1983. Modes of inhibition by acylcarnitines, adriamycin and trifluoperazine of cardiac phospholipid-sensitive calcium-dependent protein kinase. Biochem. Pharmacol. 32: 1259–1265.

    Article  CAS  Google Scholar 

  17. O'Brian, C.A., Liskamp, R.M., Solomon, D.H. and Weinstein, I.B. 1985. Inhibition of protein kinase C by tamoxifen. Cancer Res. 45: 2462–2465.

    CAS  PubMed  Google Scholar 

  18. Marx, M.H., Piantadosi, C., Noseda, A., Daniel, L.W. and Modest, E.J. 1988. Synthesis and evaluation of neoplastic cell growth inhibition of 1-N-alkylamide analogues of glycero-3-phosphocholine. J. Med. Chem. 31: 858–863.

    Article  CAS  Google Scholar 

  19. Hannun, Y.A. and Bell, R.M. 1987. Lysosphingolipids inhibit protein kinase C: Implications for sphingolipidoses. Science 235: 670–674.

    Article  CAS  Google Scholar 

  20. Mazzei, G.J., Katoh, N. and Kuo, J.F. 1982. Polymixin B is a more selective inhibition for phospholipid-sensitive Ca++-dependent protein kinase. Biochem. Biophys. Res. Commun. 109: 1129–1133.

    Article  CAS  Google Scholar 

  21. Hannun, Y.A., Foglesong, R.J. and Bell, R.M. 1989. The adriamycin-iron (III) complex is a potent inhibitor of protein kinase C. J. Biol. Chem. 264: 9960–9966.

    CAS  PubMed  Google Scholar 

  22. Omura, S., Iwai, Y., Hirano, A., Nakagawa, A., Awaya, J., Tsuchiya, H., Takahashi, Y. and Masuma, R. 1977. A new alkaloid AM-2282 of Streptomyces origin: taxonomy, fermentation, isolation and preliminary characterization. J. Antibiot. 30: 275–281.

    Article  CAS  Google Scholar 

  23. Nakano, H., Kobayashi, E., Takahashi, I., Tamaoki, T., Kuzuu, Y. and Iba, H. 1987. Staurosporine inhibits tyrosine-specific protein kinase activity of Rous sarcoma virus transforming protein p60. J. Antibiot. 40: 706–708.

    Article  CAS  Google Scholar 

  24. Fujita-Yamaguchi, Y. and Kathuria, S. 1988. Characterization of receptor tyrosine-specific protein kinases by the use of inhibitors. Staurosporine is a 100 times more potent inhibitor of insulin receptor than IGF-1 receptor. Biochem. Biophys. Res. Commun. 157: 955–962.

    Article  CAS  Google Scholar 

  25. Nakadate, T., Jeng, A.Y. and Blumberg, P.M. 1988. Comparison of protein kinase C functional assays to clarify mechanisms of inhibitor action. Biochem. Pharmacol. 37: 1541–1545.

    Article  CAS  Google Scholar 

  26. Kobayashi, E., Takahashi, I., Nakano, H. and Tamaoki, T. Staurosporine inhibits the catalytic domain of protein kinases. In preparation.

  27. Ruegg, U.T. and Burgess, G.M. 1989. Staurosporine, K-252 and UCN-01: potent but nonspecific inhibitors of protein kinases. Trends Pharmacol. Sci. 10: 218–220.

    Article  CAS  Google Scholar 

  28. Takahashi, I., Saitoh, Y., Yoshida, M., Sano, H., Nakano, H., Morimoto, M. and Tamaoki, T. 1989. II. Purification, physico-chemical properties, structural determination and biological activities. J. Antibiot. 42: 571–576.

    Article  CAS  Google Scholar 

  29. Okabe, H., Akinaga, S., Morimoto, M., Tamaoki, T. and Hirata, T. Antitumor effect of UCN-01, a novel PKC inhibitor, on tumor cell lines in vitro and in vivo, p. 413. 1990. Abstracts of the 81st Annual Meeting of the A.A.C.R.

  30. Tanida, S., Takizawa, M., Takahashi, T., Tsubotani, S. and Harada, S. 1989. TAN-999 and TAN-1030A, new indolocarbazole alkaloids with macrophage-activating properties. J. Antibiot. 42: 1619–1630.

    Article  CAS  Google Scholar 

  31. Morioka, H., Ishihara, M., Shibai, H. and Suzuki, T. 1985. Staurosporine-induced differentiation in a human neuroblastoma cell line, NB-1. Agric. Biol. Chem. 49: 1959–1963.

    CAS  Google Scholar 

  32. Oka, S., Suzuki, H. and Sata, A. 1985. Jpn. Kokai Tokkyo Koho Jp 60-188325.

  33. Sezaki, M., Sakai, T., Nakazawa, T., Takeda, U., Iwata, M., Watanabe, T., Koyama, M., Kai, F., Shomura, T. and Kojima, M. 1985. A new antibiotic SF-2370 produced by Actinomadura, J. Antibiot. 38: 1437–1439.

    Article  CAS  Google Scholar 

  34. Bush, J.A., Long, B.H., Catino, J.J. and Bradner, W.T. 1987. Production and biological activity of rebeccamycin, a novel antitumor agent, J. Antibiot. 40: 668–678.

    Article  CAS  Google Scholar 

  35. Matson, J.A., Claridge, C., Bush, J.A., Titus, J., Bradner, W.T. and Doyle, T.W. 1989. AT2433-A1, A2, B1, B2, novel antitumor antibiotic compounds produced by Actinomadura melliaura, J. Antibiot. 42: 1547–1555.

    Article  CAS  Google Scholar 

  36. Kobayashi, E., Ando, K., Nakano, H., Iida, T., Ohno, H., Morimoto, M. and Tamaoki, T. 1990. Calphostins (UCN1028), novel and specific inhibitors of protein kinase C. I. Fermentation, isolation, physicochemical properties and biological activities. J. Antibiot. 42: 1470–1474.

    Article  Google Scholar 

  37. Iida, T., Kobayashi, Yoshida, M. and Sano, H. 1990. II. Chemical structures. J. Antibiot. 42: 1476–1481.

    Google Scholar 

  38. Yoshihara, T., Shimanuki, T., Araki, T. and Sakamura, S. 1975. Phleichrome; a new phytotoxic compound by Cladosporium phlei. Agr. Biol. Chem. 39: 1683–1684.

    CAS  Google Scholar 

  39. Arnone, A., Camarda, L., Nasini, G. and Merlini, L. 1985. Secondary mould metabolites. Part 13. Fungal perylenequinones: phleichrome, isophleichrome and their endoperoxides. J. Chem. Soc. Soc. Perkin Trans. I. 1387–1392.

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  1. Kyowa Hakko Co. Ltd., Tokyo Research Laboratories, 3-6-6, Asahimachi, Machida-shi, Tokyo, 194, Japan

    Tatsuya Tamaoki & Hirofumi Nakano

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  1. Tatsuya Tamaoki
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  2. Hirofumi Nakano
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Tamaoki, T., Nakano, H. Potent and Specific Inhibitors of Protein Kinase C of Microbial Origin. Nat Biotechnol 8, 732–735 (1990). https://doi.org/10.1038/nbt0890-732

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