Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of drug inhibition of signalling molecules

Nature volume 441, pages 457–462 (2006)Cite this article

Abstract

The emergence of tumour-specific, molecularly targeted agents signifies a paradigm shift in cancer therapy, with less reliance on drugs that non-discriminately kill tumour and host cells. Although the diversity of targets giving rise to this new generation of anticancer drugs has expanded, many challenges persist in the design of effective treatment regimens. The complex interplay of signal-transduction pathways further complicates the customization of cancer treatments to target single mechanisms. However, despite uncertainty over precise or dominant mechanisms of action, especially for compounds targeting multiple gene products, emerging agents are producing significant therapeutic advances against a broad range of human cancers.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Central growth factor signalling pathways that drive pleiotropic cellular responses.
Figure 2: The protein kinase fold: ribbon diagram of MEK1 with bound ATP and PD318088.
Figure 3: Alternative binding modes of kinase inhibitors.

Similar content being viewed by others

References

  1. Johnson, J. I. et al. Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br. J. Cancer 84, 1424–1431 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Voskoglou-Nomikos, T., Pater, J. L. & Seymour, L. Clinical predictive value of the in vitro cell line, human xenograft, and mouse allograft preclinical cancer models. Clin. Cancer Res. 9, 4227–4239 (2003).

    PubMed  Google Scholar 

  3. Stehelen, D., Varmus, H. E., Bishop, J. M. & Vogt, P. K. DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260, 170–173 (1976).

    Article  ADS  Google Scholar 

  4. Brugge, J. S. & Erikson, R. L. Identification of a transformation-specific antigen induced by an avian sarcoma virus. Nature 269, 346–348 (1977).

    Article  ADS  CAS  PubMed  Google Scholar 

  5. 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  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  6. Levinson, A. D., Oppermann, H., Levintow, L, Varmus, H. E. & Bishop, J. M. Evidence that the transforming gene of avian sarcoma virus encodes a protein kinase associated with a phosphoprotein. Cell 15, 561–572 (1978).

    Article  CAS  PubMed  Google Scholar 

  7. Blume-Jensen, P. & Hunter, T. Oncogenic kinase signalling. Nature 411, 355–365 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Baselga, J. & Arteaga, C. L. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J. Clin. Oncol. 23, 2445–2459 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Jain, R. K., Duda, D. G., Clark, J. W. & Loeffler, J. S. Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nature Clin. Pract. Oncol. 3, 24–40 (2006).

    Article  CAS  Google Scholar 

  10. 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  PubMed  Google Scholar 

  11. Wang, Z. et al. Structural basis of inhibitor selectivity in MAP kinases. Structure 6, 1117–1128 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Kostich, M. et al. Human members of the eukaryotic protein kinase family. Genome Biol. 3, RESEARCH0043 (2002).

  13. Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912–1934 (2002).

    Article  ADS  CAS  PubMed  Google Scholar 

  14. 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).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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  PubMed  Google Scholar 

  16. Bain, J., McLauchlan, H., Elliott, M. & Cohen, P. The specificities of protein kinase inhibitors: an update. Biochem. J. 371, 199–204 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ohren, J. et al. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nature Struct. Biol. 11, 1192–1197 (2004).

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Pargellis, C. et al. Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nature Struct. Biol. 9, 268–272 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Wan, C. et al. Mechanism of activation of the RAF–ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116, 855–867 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Sheinerman, F. B., Giraud, E. & Laoui, A. High affinity targets of protein kinase inhibitors have similar residues at the positions energetically important for binding. J. Mol. Biol. 352, 1134–1156 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 7, 57–70 (2000).

    Article  Google Scholar 

  23. Heinrich, M. C., Blanke, C. D., Druker, B. J. & Corless, C. L. Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J. Clin. Oncol. 20, 1692–1703 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Shimizu, A. et al. The dermatofibrosarcoma protuberans-associated collagen type Iα1/platelet-derived growth factor (PDGF) B-chain fusion gene generates a transforming protein that is processed to functional PDGF-BB. Cancer Res. 59, 3719–3723 (1999).

    CAS  PubMed  Google Scholar 

  25. Gilliland, D. G. & Griffin, J. D. Role of FLT3 in leukemia. Curr. Opin. Hematol. 9, 274–281 (2002).

    Article  PubMed  Google Scholar 

  26. Cherrington, J. M., Strawn, L. M. & Shawver, L. K. in Advances in Cancer Research (eds Klein, G., VandeWoude, G. F.) 1–38 (Academic, San Diego, 2000).

    Google Scholar 

  27. Mendel, D. B. et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin. Cancer Res. 9, 327–337 (2003).

    CAS  PubMed  Google Scholar 

  28. Motzer, R. J. et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 24, 16–24 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Ebos, J. M. et al. A naturally occurring soluble form of vascular endothelial growth factor receptor 2 detected in mouse and human plasma. Mol. Cancer Res. 2, 315–326 (2004).

    CAS  PubMed  Google Scholar 

  30. Lyons, J. F., Wilhelm, S., Hibner, B. & Bollag, G. Discovery of a novel Raf kinase inhibitor. Endocrine Relat. Cancer 8, 219–225 (2001).

    Article  CAS  Google Scholar 

  31. Wilhelm, S. & Chien, D.-S. BAY 43-9006: preclinical data. Curr. Pharm. Design 8, 2255–2257 (2002).

    Article  CAS  Google Scholar 

  32. Wilhelm, S. M. et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 64, 7099–7109 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Bergers, G., Song, S., Meyer-Morse, N., Bergsland, E. & Hanahan, D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J. Clin. Invest. 111, 1287–1295 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yeon, C. H. & Pegram, M. D. Anti-erbB-2 antibody trastuzumab in the treatment of HER2-amplified breast cancer. Invest. New Drugs 23, 391–409 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Goldberg, R. M. Cetuximab. Nature Rev. Drug Discov. (suppl. 1), S10–S11 (2005).

  36. Kerr, D. G. Targeting angiogenesis in cancer: clinical development of bevacizumab. Nature Clin. Pract. Oncol. 1, 39–43 (2004).

    Article  CAS  Google Scholar 

  37. Cohen, M. H., Williams, G. A., Shridhara, R., Chen, G. & Pazdur, R. FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist 8, 303–306 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Johnson, J. R. et al. Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Clin. Cancer Res. 11, 6414–6421 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Nelson, M. H. & Dolder, C. R. Lapatinib: a novel dual tyrosine kinase inhibitor with activity in solid tumors. Ann. Pharmacother. 40, 261–269 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Fry, D. W. et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol. Cancer Ther. 3, 1427–1438 (2004).

    CAS  PubMed  Google Scholar 

  41. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).

    Article  ADS  CAS  PubMed  Google Scholar 

  42. Satyamoorthy, K. et al. Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. Cancer Res. 63, 756–759 (2003).

    CAS  PubMed  Google Scholar 

  43. Solit, D. B. et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature 439, 358–362 (2006).

    Article  ADS  CAS  PubMed  Google Scholar 

  44. Sebolt-Leopold, J. S. & Herrera, R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nature Rev. Cancer 4, 937–947 (2004).

    Article  CAS  Google Scholar 

  45. Wallace, E. M., Lyssikatos, J. P., Yeh, T., Winkler, J. D. & Koch, K. Progress towards therapeutic small molecule MEK inhibitors for use in cancer therapy. Curr. Topics Med. Chem. 5, 215–229 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  47. Tamborini, E. et al. A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. Gastroenterology 127, 294–299 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Kobayashi, S. et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 352, 786–792 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. O'Hare, T., Corbin, A. S. & Druker, B. J. Targeted CML therapy: controlling drug resistance, seeking cure. Curr. Opin. Genet. Dev. 16, 92–99 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Adrian, F. J. et al. Allosteric inhibitors of Bcr–abl-dependent cell proliferation. Nature Chem. Biol. 2, 95–102 (2006).

    Article  CAS  Google Scholar 

  51. Wang, Y. et al. A role for K-ras in conferring resistance to the MEK inhibitor, CI-1040. Neoplasia 7, 336–347 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Downward, J. Signatures guide drug choice. Nature 439, 274–275 (2006).

    Article  ADS  CAS  PubMed  Google Scholar 

  53. She, Q-B. et al. The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell 8, 287–297 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Herbst, R. S. et al. Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer. J. Clin. Oncol. 23, 2544–2555 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Hainsworth, J. D. et al. Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J. Clin. Oncol. 23, 7889–7896 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Sawyers, C. Targeted cancer therapy. Nature 432, 294–297 (2004).

    Article  ADS  CAS  PubMed  Google Scholar 

  57. Canagarajah, B. J., Khokhlatchev, A., Cobb, M. H. & Goldsmith, E. J. Activation mechanism of the MAP kinase ERK2 by dual phosphorylation. Cell 90, 859–869 (1997).

    Article  CAS  PubMed  Google Scholar 

  58. Adams, J. A. Activation loop phosphorylation and catalysis in protein kinases: is there functional evidence for the autoinhibitor model? Biochemistry 42, 601–607 (2003).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank D. Leopold, R. Herrera and S. Eck for their thoughtful comments. We would like to express special gratitude to J. Ohren for his generous provision of Figs 2 and 3 as well as helpful feedback.

Author information

Authors and Affiliations

  1. Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, 48105, Michigan, USA

    Judith S. Sebolt-Leopold

  2. Pfizer Research Technology Center, 620 Memorial Drive, Cambridge, 02139, Massachusetts, USA

    Jessie M. English

Authors
  1. Judith S. Sebolt-Leopold
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jessie M. English
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Judith S. Sebolt-Leopold.

Ethics declarations

Competing interests

Both authors are employees of Pfizer Global R&D and own Pfizer stock/shares.

Editor's note: The author has declared interests in Pfizer, which has co-sponsored this Nature Insight. However all editorial content was commissioned entirely independently of this partnership.

Additional information

Author Information Reprints and permissions information is available at npg.nature.com/reprintsandpermissions.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sebolt-Leopold, J., English, J. Mechanisms of drug inhibition of signalling molecules. Nature 441, 457–462 (2006). https://doi.org/10.1038/nature04874

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature04874

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing