Case histories, magic bullets and the state of drug discovery

Abstract

The case histories of five modern drugs are taken as a basis for reflection on the state of drug discovery. Two issues intimately associated with drug research are highlighted: the nature of the intellectual process leading to new discoveries; and the possibility that the principle of selective efficacy, which has guided drug research from its beginnings, might need modification, at least in some areas of pharmacotherapy.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Cyclooxygenases and prostanoid synthesis.
Figure 2: Multiple sclerosis and the role of α4β1 integrin.
Figure 3: Chemical structure of imatinib.
Figure 4: VEGF signalling and cancer: a simplified view.
Figure 5: Viral entry in the HIV life cycle.

References

  1. 1

    Flower, R. J. The development of COX-2 inhibitors. Nature Rev. Drug Discov. 2, 179–191 (2003).

    CAS  Article  Google Scholar 

  2. 2

    Rosen, G. D., Birkenmaier, T. M., Raz, A. & Holtzman, M. J. Identification of a cyclooxygenase-related gene and its potential role in prostaglandin formation. Biochem. Biophys. Res. Commun. 164, 1358–1365 (1989).

    CAS  Article  Google Scholar 

  3. 3

    Kujubu, D. A., Fletcher, B. S., Varnuzu, B. C., Lim, R. W. & Herschmann, H. R. TISIO, a phorbol ester tumor promotor-inducible mRNA from Swiss 3T3 cells encodes a novel prostaglandin synthase/cyclooxygenase homologue. J. Biol. Chem. 266, 12866–12872 (1991).

    CAS  PubMed  Google Scholar 

  4. 4

    Flower, R. J. & Vane, J. R. Selectivity of non-steroidal anti-inflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc. Natl Acad. Sci. USA 90, 11693–11697 (1993).

    Article  Google Scholar 

  5. 5

    Smith, W. L., DeWitt, D. L. & Garavito, R. M. Cyclooxygenases: structural and molecular biology. Am. Rev. Biochem. 69, 145–182 (2000).

    CAS  Article  Google Scholar 

  6. 6

    FitzGerald, G. A. & Patrono, C. The coxibs, selective inhibitors of cyclooxygenase 2. N. Engl. J. Med. 345, 433–442 (2001).

    CAS  Article  Google Scholar 

  7. 7

    Warner, T. D. & Mitchell, J. A. Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J. 18, 790–804 (2004)

    CAS  Article  Google Scholar 

  8. 8

    Mycek, M., Harvey, R. A. & Champe, P. Pharmacology 2nd edn, p404 (Lippincott, New York, 2000).

    Google Scholar 

  9. 9

    Vane, J. R., Bakhle Y. S. & Botting, R. M. Cyclooxygenase 1 and 2. Annu. Rev. Pharm. Toxicol. 38, 97–120 (1998).

    CAS  Article  Google Scholar 

  10. 10

    Bombardier, C. et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N. Engl. J. Med. 343, 1520–1528 (2000).

    CAS  Article  Google Scholar 

  11. 11

    Silverstein, F. E. et al. Gastrointestinal toxicity with celocoxib vs non-steroidal and anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 284, 1247–1255 (2000).

    CAS  Article  Google Scholar 

  12. 12

    Schnitzer, T. J. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomized controlled trial. Lancet 64, 665–674 (2004).

    Article  Google Scholar 

  13. 13

    Solomon, S. D. et al. Adenoma Prevention with Celecoxib (APC) study investigators. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N. Engl. J. Med. 352, 1071–1080 (2005).

    CAS  Article  Google Scholar 

  14. 14

    Ott, E. et al. Efficacy and safety of the cyclooxygenase-2 inhibitors parecoxib and valdecoxib in patients undergoing coronary bypass surgery. J. Thorac. Cardiovasc. Surgery 125, 1481–1492 (2003).

    CAS  Article  Google Scholar 

  15. 15

    An audience with... Steven Nissen. Nature Rev. Drug Discov. 5, 98 (2006).

  16. 16

    Mitchell, J. A. & Warner, T. D. COX isoforms in the cardiovascular system: understanding the activities of non-steroidal anti-inflammatory drugs. Nature Rev. Drug Discov. 5, 75–86 (2006).

    CAS  Article  Google Scholar 

  17. 17

    Mitchell, J. A. & Evans, T. W. Cyclooxygenase-2 as a therapeutic target. Inflamm. Res. 47 (Suppl. 2), S88–S92 (1998).

    CAS  Article  Google Scholar 

  18. 18

    Steinman, L. Blocking adhesion molecules as a therapy for multiple sclerosis: natalizumab. Nature Rev. Drug Discov. 4, 510–518 (2005).

    CAS  Article  Google Scholar 

  19. 19

    Yednock, T. A. et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against the α4β1 integrin. Nature 356, 63–66 (1992).

    CAS  Article  Google Scholar 

  20. 20

    Engelhardt, B. et al. The development of experimental autoimmune encephalomyelitis in the mouse requires α4-integrin but not α4β7-integrin. J. Clin. Invest. 102, 2096–2105 (1998).

    CAS  Article  Google Scholar 

  21. 21

    Leger, O. J. et al. Humanization of a mouse antibody against human α4 integrin: a potential therapeutic for the treatment of multiple sclerosis. Hum. Antibodies 8, 3–16 (1997).

    CAS  Article  Google Scholar 

  22. 22

    Miller, D. H. et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 348, 15–23 (2003).

    CAS  Article  Google Scholar 

  23. 23

    Sheridan, C. Third Tysabri adverse case hits drug class. Nature Rev. Drug Discov. 4, 357–358 (2005).

    CAS  Article  Google Scholar 

  24. 24

    Capdeville, R., Buchdunger, E., Zimmermann, J. & Matter, A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nature Rev. Drug Discov. 1, 493–502 (2002).

    CAS  Article  Google Scholar 

  25. 25

    Vlahovic, G. et al. Activation of tyrosine kinases in cancer. The Oncologist 8, 531–538 (2003).

    CAS  Article  Google Scholar 

  26. 26

    Cohen, P. Protein kinases, the major drug targets of the 21st century? Nature Rev. Drug Discov. 1, 309–316 (2002).

    CAS  Article  Google Scholar 

  27. 27

    Melnikova, I. & Golden, J. Targeting protein kinases. Nature Rev. Drug Discov. 3, 993–994 (2004).

    CAS  Article  Google Scholar 

  28. 28

    Ferrara, N. et al. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nature Rev. Drug Discov. 3, 391–400 (2004).

    CAS  Article  Google Scholar 

  29. 29

    Kim, K. J. et al. Inhibition for vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo. Nature 362, 841–844 (1993).

    CAS  Article  Google Scholar 

  30. 30

    Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil and leukovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335–2342 (2004).

    CAS  Article  Google Scholar 

  31. 31

    Ellis, L. M. & Kirkpatrick, P. Bevacizumab. Nature Rev. Drug Discov. 4, S8–S9 (2005).

    Article  Google Scholar 

  32. 32

    Jain, R. K. Normalization of tumour vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).

    CAS  Article  Google Scholar 

  33. 33

    Matthews, T. et al. Enfuvirtide: the first therapy to inhibit the entry of HIV-1 into host CD4 lymphocytes. Nature Rev. Drug Discov. 3, 215–225 (2004).

    CAS  Article  Google Scholar 

  34. 34

    Matthews, T. J. et al. Structural rearrangements in the transmembrane glycoprotein after receptor binding. Immunol. Rev. 140, 93–104 (1994).

    CAS  Article  Google Scholar 

  35. 35

    Lalezari, J. P. et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N. Engl. J. Med. 348, 2175–2185 (2003).

    CAS  Article  Google Scholar 

  36. 36

    Lazzarin, A. et al. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N. Engl. J. Med. 348, 2186–2195 (2003).

    CAS  Article  Google Scholar 

  37. 37

    Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents [online], <http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL04072005001.pdf> (2005).

  38. 38

    Horobin, D. F. Modern biomedical research: an internally self-consistent universe with little contact with medical reality? Nature Rev. Drug Discov. 2, 151–154 (2003).

    Article  Google Scholar 

  39. 39

    Butcher, E. C. Can cell systems biology rescue drug discovery? Nature Rev. Drug Discov. 4, 461–466 (2005).

    CAS  Article  Google Scholar 

  40. 40

    Van der Greef, J. & McBurney, R. N. Rescuing drug discovery: in vivo systems pathology and systems pharmacology. Nature Rev. Drug Discov. 4, 961–966 (2005).

    CAS  Article  Google Scholar 

  41. 41

    Kubinyi, H. Drug research: myths, hype and reality. Nature Rev. Drug Discov. 2, 665–668 (2003).

    CAS  Article  Google Scholar 

  42. 42

    Noseworthy, J. & Kirkpatrick, P. Natalizumab. Nature Rev. Drug Discov. 4, 101–102 (2005).

    CAS  Article  Google Scholar 

  43. 43

    Kilby, J. M. et al. Potent suppression of HIV-1 replication by T-20, a peptide inhibitor of gp41-mediated virus entry. Nature Med. 4, 1302–1307 (1998).

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

DATABASES

OMIM

Rheumatoid arthritis

Cancer.gov

Chronic myeloid leukaemia

Colorectal cancer

Non-small-cell lung cancer

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Drews, J. Case histories, magic bullets and the state of drug discovery. Nat Rev Drug Discov 5, 635–640 (2006). https://doi.org/10.1038/nrd2084

Download citation

Further reading

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