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Protein kinases — the major drug targets of the twenty-first century?

Nature Reviews Drug Discovery volume 1, pages 309–315 (2002)Cite this article

Abstract

Protein phosphorylation regulates most aspects of cell life, whereas abnormal phosphorylation is a cause or consequence of disease. A growing interest in developing orally active protein-kinase inhibitors has recently culminated in the approval of the first of these drugs for clinical use. Protein kinases have now become the second most important group of drug targets, after G-protein-coupled receptors. Here, I give a personal view of some of the most important advances that have shaped this field.

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Figure 1
Figure 2: Chemical structures of some small-molecule inhibitors of protein kinases that have been approved or are undergoing human clinical trials.
Figure 3: Basis for the specificity of two ATP-competitive protein-kinase inhibitors.

References

  1. Cohen, P. The origins of protein phosphorylation. Nature Cell Biol. (in the press).

  2. Collett, M. S. & Erikson, R. L. Protein kinase activity associated with the avian sarcoma virus src gene product. Proc. Natl Acad. Sci. USA 75, 2021–2024 (1978).

    Article  CAS  Google Scholar 

  3. Castagna, M. et al. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumour-promoting phorbol esters. J. Biol. Chem. 257, 7847–7851 (1982).

    CAS  Google Scholar 

  4. Kishimoto, A., Takai, Y., Mori, T., Kikkawa, U. & Nishizuka, Y. Activation of calcium and phospholipid-dependent protein kinase by diacylglycerol, its possible relation to phosphatidylinositol turnover. J. Biol. Chem. 255, 2273–2276 (1980).

    CAS  Google Scholar 

  5. Hidaka, H., Inagaki, M., Kawamoto, S. & Sasaki, Y. Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. Biochemistry 23, 5036–5041 (1984).

    Article  CAS  Google Scholar 

  6. Shibuya, M. et al. Effect of AT877 on cerebral vasospasm after aneurysmal subarachnoid haemorrhage. J. Neurosurg. 76, 571–577 (1992).

    Article  CAS  Google Scholar 

  7. Asano, T., Ikegaki, I., Satoh, S., Seto, M. & Sasaki, Y. A protein kinase inhibitor, fasudil (AT-877); a novel approach to signal transduction therapy. Cardiovascular Drug Rev. 16, 76–87 (1998).

    Article  CAS  Google Scholar 

  8. Davies, S. P., Reddy, H., Caivano, M. & Cohen, P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J. 351, 95–105 (2000).

    Article  CAS  Google Scholar 

  9. Kimura K. et al. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 273, 245–248 (1996).

    Article  CAS  Google Scholar 

  10. Uehata, M. et al. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature 389, 990–994 (1997).

    Article  CAS  Google Scholar 

  11. Tamaoki, T. et al. Staurosporine, a potent inhibitor of phospholipid/Ca2+ dependent protein kinase. Biochem. Biophys. Res. Commun. 135, 397–402 (1986).

    Article  CAS  Google Scholar 

  12. Davis, P. D. et al. Potent selective inhibitors of protein kinase C. FEBS Lett. 259, 61–63 (1992).

    Article  Google Scholar 

  13. Toullec, D. et al. The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. J. Biol. Chem. 266, 15771–15781 (1991).

    CAS  Google Scholar 

  14. Alessi, D. R. The protein kinase C inhibitors Ro 318220 and GF 109203X are equally potent inhibitors of MAPKAP-K1β (Rsk-2) and p70 S6 kinase. FEBS Lett. 402, 121–123 (1997).

    Article  CAS  Google Scholar 

  15. Graves, P. R. et al. The CHK1 protein kinase and the CDC25C regulatory pathways are targets of the anticancer agent UCN-01. J. Biol. Chem. 275, 5600–5605 (2000).

    Article  CAS  Google Scholar 

  16. Fabbro, D. et al. PKC412, a protein kinase inhibitor with a broad therapeutic potential. Anticancer Drug Res. 15, 17–28 (2000).

    CAS  Google Scholar 

  17. Engel, G. L., Farid, N. A., Faul, M. M., Richardson, L. A. & Winneroski, L. L. Salt form selection and characterisation of LY 333531 mesylate monohydrate. Int. J. Pharm. 198, 239–247 (2000).

    Article  CAS  Google Scholar 

  18. Maroney, A. C. et al. CEP-1347 (KT7515), a semisynthetic inhibitor of the mixed lineage kinase family. J. Biol. Chem. 276, 25302–25308 (2001).

    Article  CAS  Google Scholar 

  19. Knighton, D. R. et al. Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science 253, 407–414 (1991).

    Article  CAS  Google Scholar 

  20. Liu, J. et al. Calcineurin is a common target of cyclophilin–cyclosporin A and FKBP– FK506 complexes. Cell 66, 807–815 (1991).

    Article  CAS  Google Scholar 

  21. Stewart, A. A., Ingebritsen, T. S., Manalan, A., Klee, C. B. & Cohen, P. Discovery of a Ca2+ and calmodulin-dependent protein phosphatase: probable identity with calcineurin (CaM-BP80). FEBS Lett. 137, 80–84 (1982).

    Article  CAS  Google Scholar 

  22. Garber, K. Rapamycin's resurrection: a new way to target the cancer cell cycle. J. Natl Cancer Inst. 93, 1517–1519 (2001).

    Article  CAS  Google Scholar 

  23. Yu, K. et al. mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr. Relat. Cancer 8, 249–258 (2001).

    Article  Google Scholar 

  24. Heitman, J. Movva, N. R. & Hall, M. N. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253, 905–909 (1991).

    Article  CAS  Google Scholar 

  25. Neshat, M. S. et al. Enhanced sensitivity of PTEN-deficient tumours to inhibition of FRAP/mTOR. Proc. Natl Acad. Sci. USA 98, 10314–10319 (2001).

    Article  CAS  Google Scholar 

  26. Podsypanina, K. et al. An inhibitor of mTOR reduces neoplasia and normalises p70/S6 kinase activity in Pten+/− mice. Proc. Natl Acad. Sci. USA 98, 10320–10325 (2001).

    Article  CAS  Google Scholar 

  27. Adams, J. L., Badger, A. M., Kumar, S. & Lee, J. C. p38 MAP kinase: molecular target for the inhibition of proinflammatory cytokines. Prog. Med. Chem. 38, 1–60 (2001).

    Article  CAS  Google Scholar 

  28. Lee, J. C., Griswold, D. E., Votta, B. & Hanna, N. Inhibition of monocyte IL-1 production by the anti-inflammatory compound SK&F 86002. Int. J. Immunopharmacol. 10, 835–843 (1988).

    Article  CAS  Google Scholar 

  29. Lee, J. C. et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372, 739–746 (1994).

    Article  CAS  Google Scholar 

  30. Han, J., Lee, J. D., Bibbs, L. & Ulevitch R. J. A MAP kinase targetted by endotoxin and hyperosmolarity in mammalian cells. Science 265, 808–811 (1994).

    Article  CAS  Google Scholar 

  31. Rouse, J. et al. A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell 78, 1027–1037 (1994).

    Article  CAS  Google Scholar 

  32. Freshney, N. W. et al. Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. Cell 78, 1039–1049 (1994).

    Article  CAS  Google Scholar 

  33. Cuenda, A. et al. SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Lett. 364, 229–233 (1995).

    Article  CAS  Google Scholar 

  34. Tong, L. et al. A highly specific inhibitor of human p38 MAP kinase binds in the ATP pocket. Nature Struct. Biol. 4, 311–316 (1997).

    Article  CAS  Google Scholar 

  35. Eyers, P. A., Craxton, M., Morrice, N., Cohen, P. & Goedert, M. Conversion of SB 203580-insensitive MAP kinase family members to drug-sensitive forms by a single amino-acid substitution. Chem. Biol. 5, 321–328 (1998).

    Article  CAS  Google Scholar 

  36. Gum, R. J. et al. Acquisition of sensitivity of stress-activated protein kinases to the p38 inhibitor, SB 203580, by alteration of one or more amino acids within the ATP-binding pocket. J. Biol. Chem. 273, 15605–15610 (1998).

    Article  CAS  Google Scholar 

  37. Mohammadi, M. et al. Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. Science 276, 955–960 (1997).

    Article  CAS  Google Scholar 

  38. De Azevedo, W. F. et al. Inhibition of cyclin-dependent protein kinases by purine analogues: crystal structure of human Cdk2 complexed with roscovitine. Eur. J. Biochem. 243, 518–526 (1997).

    Article  CAS  Google Scholar 

  39. Gray, N. S. et al. Exploiting chemical libraries, structure and genomics in the search for kinase inhibitors. Science 281, 533–538 (1998).

    Article  CAS  Google Scholar 

  40. Ward, W. H. et al. Epidermal growth factor receptor tyrosine kinase. Investigation of catalytic mechanism, structure-based searching and discovery of a potent inhibitor. Biochem. Pharmacol. 48, 659–666 (1994).

    Article  CAS  Google Scholar 

  41. Fry, D. W. et al. A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science 265, 1093–1095 (1994).

    Article  CAS  Google Scholar 

  42. Osherov, N. & Levitski, A. Epidermal-growth-factor-dependent activation of the src-family kinases. Eur. J. Biochem. 225, 1047–1053 (1994).

    Article  CAS  Google Scholar 

  43. Morin, M. J. From oncogene to drug: development of small molecule tyrosine kinase inhibitors as anti-tumor and anti-angiogenic agents. Oncogene 19, 6574–6583 (2000).

    Article  CAS  Google Scholar 

  44. Senderowicz, A. M. Small molecule modulators of cyclin-dependent kinases for cancer therapy. Oncogene 19, 6600–6606 (2000).

    Article  CAS  Google Scholar 

  45. Hoessel, R. et al. Indirubin, the active constituent of a chinese antileukaemia medicine, inhibits cyclin-dependent kinases. Nature Cell Biol. 1, 60–67 (1999).

    Article  CAS  Google Scholar 

  46. Buchdunger, E. et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res. 56, 100–104 (1996).

    CAS  Google Scholar 

  47. Druker, B. J. et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells. Nature Med. 2, 561–566 (1996).

    Article  CAS  Google Scholar 

  48. Druker, B. J. et al. Efficacy and safety of a specific inhibitor of the BCR–ABL tyrosine kinase in chronic myeloid leukaemia. N. Engl. J. Med. 344, 1031–1037 (2001).

    Article  CAS  Google Scholar 

  49. Druker, B. J. & Lydon, N. Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukaemia. J. Clin. Invest. 105, 3–7 (2000).

    Article  CAS  Google Scholar 

  50. Schindler, T. et al. Structural mechanism of STI-571 inhibition of Abelson tyrosine kinase. Science 289, 1938–1942 (2000).

    Article  CAS  Google Scholar 

  51. Buchdunger, E. et al. Abl protein-tyrosine kinase inhibitor, STI-571, inhibits in vitro signal transduction mediated by c-Kit and PDGF receptors. J. Pharmacol. Exp. Ther. 295, 139–145 (2000).

    CAS  Google Scholar 

  52. Joensuu, H. et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N. Engl. J. Med. 344, 1052–1056 (2001).

    Article  CAS  Google Scholar 

  53. Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J. & Saltiel, A. R. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc. Natl Acad. Sci. USA 92, 7686–7689 (1995).

    CAS  Google Scholar 

  54. Alessi, D. R., Cuenda, A., Cohen, P., Dudley, D. T. & Saltiel, A. R. PD98059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J. Biol. Chem. 270, 27489–27494 (1995).

    Article  CAS  Google Scholar 

  55. Favata, M. F. et al. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J. Biol. Chem. 273, 18623–18632 (1998).

    Article  CAS  Google Scholar 

  56. Sebolt-Leopold, J. S. et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nature Med. 5, 810–816 (1999).

    Article  CAS  Google Scholar 

  57. Brown, E. J. et al. Control of p70 S6 kinase by kinase activity of FRAP in vivo. Nature 377, 441–446 (1995).

    Article  CAS  Google Scholar 

  58. Eyers, P. A., van den Ijssel, P., Quinlan, R. A., Goedert, M. & Cohen, P. Use of a drug-resistant mutant of stress-activated protein kinase 2a/p38 to validate the in vivo specificity of SB 203580 FEBS Lett. 451, 191–196 (1999).

    Article  CAS  Google Scholar 

  59. Gorre, M. E. et al. Clinical resistance to STI-571 cancer therapy caused by BCR–ABL gene mutation or amplification. Science 293, 876–880 (2001).

    Article  CAS  Google Scholar 

  60. Frame, S., Cohen, P. & Biondi, R. M. A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol. Cell 7, 1321–1327 (2001).

    Article  CAS  Google Scholar 

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Acknowledgements

I thank J. Adams, S. Cartlidge, R. Ford, S. Jakes, B. Machin and N. Lydon for helpful discussions. I apologise to the many scientists whose important discoveries could not be included or referenced in this article because of space restrictions. The work carried out in my laboratory is supported by the UK Medical Research Council, The Royal Society of London, Diabetes UK, The Louis Jeantet Foundation, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, NovoNordisk and Pfizer.

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  1. Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, Scotland, UK

    Philip Cohen

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Cancer.gov

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LocusLink

ABL

BCR

calcineurin

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CDK2

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cyclophilin

EGF

EGFR

FGFR

FKBP

IL-1

IL-2

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TNF

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Cohen, P. Protein kinases — the major drug targets of the twenty-first century?. Nat Rev Drug Discov 1, 309–315 (2002). https://doi.org/10.1038/nrd773

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