Advertisement

Anticancer Drug Discovery and Development

  • Francesco Colotta
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 610)

The marked contribution of molecular oncology within the past three decades has revealed that the multistage process of cancer growth and progression is attributable to the accumulation of genetic and epigenetic alterations. Malignant carcinomas display genetic alterations in multiple oncogenes and tumor suppressor genes, harbor epigenetic modifications that result in altered expression of several genes and contain chromosomal alterations, including aneuploidy and loss of heterozigosity (Vogelstein and Kinzler 1993; Lengauer, Kinzler, and Vogelstein 1998).

Keywords

Nuclear Magnetic Resonance Drug Discovery Virtual Screening Target Modulation Drug Development Process 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Bell, S. P. and Dutta, A. (2002) DNA replication in eukaryotic cells. Ann. Rev. Biochem. 71, 333–374.PubMedCrossRefGoogle Scholar
  2. Benson, J. D., Chen, Y. P., Cornell-Kennon, S. A., Dorsch, M., Kim, S., Leszczyniecka, M., Sellers, W. R. and Lengauer, C. (2006) Validating cancer drug targets. Nature. 441, 451–456.PubMedCrossRefGoogle Scholar
  3. Collins, I. and Workman, P. (2006) New approaches to molecular cancer therapeutics. Nat. Chem. Biol. 2, 689–700.PubMedCrossRefGoogle Scholar
  4. Dalvit, C., Flocco, M., Veronesi, M. and Stockman, B. I. (2002) Fluorine-NMR competition binding experiments for high-throughput screening of large compound mixtures. Comb. Chem. & HTS. 5, 605–611.Google Scholar
  5. Dalvit, C., Fagemess, P. E., Hadden, D. T. A., Sarver, R. W. and Stockman, B. I. (2003) Fluorine-NMR experiments for high-throughput screening: theoretical aspects, practical considerations, and range of applicability. J. Am. Chem. Soc. 125, 7696–7703.PubMedCrossRefGoogle Scholar
  6. Dalvit, C., Ardini, E., Flocco, M., Fogliatto, G. P., Mongelli, N. and Veronesi, M. (2003) A general NMR method for rapid, efficient, and reliable biochemical screening. J. Am. Chem. Soc. 125, 14620–14625.PubMedCrossRefGoogle Scholar
  7. Dalvit, C., Ardini, E., Fogliatto, G. P., Mongelli, N. and Veronesi, M. (2004) Reliable high-throughput functional screening with 3-FABS. Drug Discov. Today 9, 595–602.PubMedCrossRefGoogle Scholar
  8. Dalvit, C., Mongelli, N., Papeo, G., Giordano, P., Veronesi, M., Moskau, D. and Kúmmerle, R. (2005) Sensitivity improvement in 19F NMR-based screening experiments: theoretical considerations and experimental applications. J. Am Chem. Soc. 127, 13380–13385.PubMedCrossRefGoogle Scholar
  9. Dalvit, C., Caronni, D., Mongelli, N., Veronesi, M. and Vulpetti, A. (2006) NMR-based quality control approach for the identification of false positives and false negatives in high throughput screening. Curr. Drug Disc. Tech. 3, 115–124.CrossRefGoogle Scholar
  10. Degrassi, A., Russo, M., Scanziani, E., Giusti, A., Texido, G., Ceruti, R. and Pesenti, E. (2006) Magnetic resonance imaging and histopathological characterization of prostate tumors in TRAMP mice as model for preclinical trials. Prostate. 67, 396–404.CrossRefGoogle Scholar
  11. Fabbro, D., Parkinson, D. and Matter, A. (2002) Protein tyrosine kinase inhibitors: new treatment modalities? Curr. Opin. Pharmacol. 2, 374–381.PubMedCrossRefGoogle Scholar
  12. Fancelli, D. and Moll, J. (2005) Inhibitors of Aurora kinases for the treatment of cancer. Expert Opin. Ther. Patents 15, 1169–1182.CrossRefGoogle Scholar
  13. Green, M. R. (2004) Targeting targeted therapy. N. Engl. J. Med. 350, 2191–2193.PubMedCrossRefGoogle Scholar
  14. Hennessy, B. T., Smith D. L., Ram, P. T., Lu, Y. and Mills, G. B. (2005) Exploiting the PI3K/AKT pathway for cancer drug discovery. Nature 4, 988–1004.CrossRefGoogle Scholar
  15. Hooft van Huijsduijnen, R. and Rommel, C. (2006) De-compartmentalizing target validation – thinking outside the pipeline boxes. J. Mol. Med. 84, 802–813.PubMedCrossRefGoogle Scholar
  16. Jackson, J. R., Patrick, D. R., Dar, M. M. and Huang, P. S. (2007) Targeted anti-mitotic therapies: can we improve on tubulin agents? Nat. Rev. Cancer 7, 107–117.PubMedCrossRefGoogle Scholar
  17. Jiang, W. and Hunter, T. (1997) Identification and characterization of a human protein kinase related to budding yeast Cdc7p. Proc. Natl. Acad. Sci. USA 94, 14320–14325.PubMedCrossRefGoogle Scholar
  18. Johnson, L., Mercer, K., Greenbaum, D., Bronson, R. T., Crowley, D., Tuveson, D. A. and Jacks, T. (2001) Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410, 1111.PubMedCrossRefGoogle Scholar
  19. Kamb, A., Wee, S. and Langauer C. (2007) Why is cancer drug discovery so difficult? Nat. Rev. Drug Discov. 6, 115–120.PubMedCrossRefGoogle Scholar
  20. Krause, D. S. and Van Etten, R. A. (2005) Tyrosine kinases as targets for cancer therapy. N. Engl. J. Med. 353, 172–187.PubMedCrossRefGoogle Scholar
  21. Lei, M., Kawasaki, Y., Young, M. R., Kihara, M., Sugino, A. and Tye, B. K. (1997) Mcm2 is a target of regulation by Cdc7-Dbf4 during the initiation of DNA synthesis. Genes Dev. 11, 3365–3374.PubMedCrossRefGoogle Scholar
  22. Lengauer, C., Kinzler, K. W. and Vogelstein B. (1998) Genetic instabilities in human cancers. Nature 396, 643–649.PubMedCrossRefGoogle Scholar
  23. Lewis, J. S., Achilefu, S., Garbow, J. R., Laforest, R. and Welch, M. J. (2002) Small animal imaging: current technology and perspectives for oncological imaging. Eur. J. Cancer 38, 2173–2188.PubMedCrossRefGoogle Scholar
  24. Lyne, P. D. (2002) Structure-based virtual screening: an overview. Drug. Discov. Today 7, 1047–1055.PubMedCrossRefGoogle Scholar
  25. Montagnoli, A., Tenca, P., Sola, F., Carpani, D., Brotherton, D., Albanese, C. and Santocanale, C. (2004) Cdc7 inhibition reveals a p53-dependent replication checkpoint that is defective in cancer cells. Cancer Res. 64, 7110–7116.PubMedCrossRefGoogle Scholar
  26. Montagnoli, A., Valsasina, B., Brotherton, D., Troiani, S., Rainoldi, S., Tenca, P., Molinari, A. and Santocanale, C. (2006) Identification of Mcm2 Phosphorylation Sites by S-phase-regulating Kinases. J. Biol. Chem. 281, 10281–10290.PubMedCrossRefGoogle Scholar
  27. Nature Biotech, (2005) A dose of reality for rational therapies. Nat. Biotech. 23, 267.CrossRefGoogle Scholar
  28. Overington, J. P., Al-Lazikani, B. and Hopkins, A. L. (2006) How many drug targets are there? Nat. Rev. Drug Disc. 5, 993–996.CrossRefGoogle Scholar
  29. Pegram, M. D., Pietras, R., Bajamonde, A., Klein, P. and Fyfe, G. (2005) Targeted therapy: wave of the future. J. Clin. Oncol. 23, 1776–1781.PubMedCrossRefGoogle Scholar
  30. Sachdev, D. and Yee, D. (2007) Disrupting insulin-like growth factor signalling as a potential cancer therapy. Mol. Canc. Ther. 6, 1–12.CrossRefGoogle Scholar
  31. Sager, J. A. and Lengauer, C. (2003) New paradigms for cancer drug discovery? Canc. Biol. & Ther. 2, 178–181.Google Scholar
  32. Schwartz, G. K. and Shah, M. A. (2005) Targeting the cell cycle: a new approach to cancer therapy. J. Clin. Oncol. 23, 9408–9421.PubMedCrossRefGoogle Scholar
  33. Sebolt-Leopold, J. S. and English, J. M. (2006) Mechanisms of drug inhibition of signalling molecules. Nature. 441, 457–462.PubMedCrossRefGoogle Scholar
  34. Shapiro, G. I. (2006) Cyclin-Dependent kinase pathways as targets for cancer treatment. J. Clin. Oncol. 24, 1770–1783.PubMedCrossRefGoogle Scholar
  35. Strebhardt, K. and Ullrich, A. (2006) Targeting polo-kinase 1 for cancer therapy. Nat. Rev. Cancer. 6, 321–330.PubMedCrossRefGoogle Scholar
  36. Suggitt, M. and Bibby, M. C. (2005) Fifty years of preclinical anticancer drug screening: empirical to target-driven approaches. Clin. Can. Res. (11) 971–981.Google Scholar
  37. Trosset, J. Y., Dalvit C., Knapp, S., Fasolini M., Veronesi, M., Mantegani S., Gianellini M., Catana C., Sundström M., Stouten P. F. W. and Moll J. K. (2006) Inhibition of protein-protein interactions: the discovery of drug-like beta-catenin inhibitors by combining virtual and biophysical screening. Proteins 64, 60–67.PubMedCrossRefGoogle Scholar
  38. Vogelstein, B. and Kinzler K. W. (1993) The multi-step nature of cancer. Trends Genet. 9, 138–141.PubMedCrossRefGoogle Scholar
  39. Weinstein, I. B. and Joe, A. K. (2006) Mechanisms of disease: oncogene addiction – a rationale for molecular targeting in cancer therapy. Nat. Clin. Pract. Onc. 3, 448–457.CrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Francesco Colotta
    • 1
  1. 1.Vice President, OncologyNerviano Medical SciencesNerviano (Milan)Italy

Personalised recommendations