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Emerging Molecular Therapies

Small-Molecule Drugs

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Principles of Molecular Oncology

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Abstract

The discovery and development of anticancer agents is undergoing revolutionary change. This change is characterized by the rapid transition from the classic cytotoxic and hormonal agents of the past toward drugs that are designed specifically to correct the precise molecular abnormalities that are responsible for the causation and progression of human tumors. Three major factors are contributing to this paradigm shift. The first is the recognition that further refinement of classic agents will not result in a stepjump in clinical utility. The second factor is our increasingly detailed understanding of the molecular pathology of cancer in terms of the genetic mutations, altered gene expression, and the resultant deregulation of cognate biochemical pathways. The third factor is the range of technologic breakthroughs used to accelerate contemporary drug discovery, particularly genomics, high-throughput screening, combinatorial chemistry, and modern structural biology.

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References

  1. Workman P. Introduction: new anticancer drug design and discovery based on advances in molecular oncology. Semin Cancer Biol. 1992; 3: 329–33.

    PubMed  CAS  Google Scholar 

  2. Bishop JM. Molecular themes in oncogenesis. Cell. 1991; 64: 235–48.

    Article  PubMed  CAS  Google Scholar 

  3. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature. 1998; 396: 643–9.

    Article  PubMed  CAS  Google Scholar 

  4. Stevens MFG. Is there a future for the small molecule in developmental cancer therapy? In: The Search for New Anticancer Drugs. ( Waring MJ, Ponder BAJ, eds.), Kluwer, Dordsecht, 1992, pp. 1–17.

    Chapter  Google Scholar 

  5. Jain RK. Deliveryof novel therapeutic agents in tumors: physiological barriers and strategies. J Natl Cancer Inst. 1989; 81: 570–6.

    Article  PubMed  CAS  Google Scholar 

  6. PhRMA Web site. Available at:http://www.phrma.org. Accessed May 4, 1999.

  7. Food and Drug Administration Web Site. Available at:http://www.fda.gov/fdae/special/ne. Accessed May 4, 1999.

  8. Rowinsky EK, Donehower RC. Drug therapy: paclitaxel (Taxol®). N Engl J Med. 1995; 332: 1004–14.

    Article  PubMed  CAS  Google Scholar 

  9. Lander ES. The new genomics: global views of biology. Science. 1996; 274: 536–9.

    Article  PubMed  CAS  Google Scholar 

  10. Nat Genet. (Suppl.) 21, January 1999.

    Google Scholar 

  11. Collins FS, Patrinos A, Jordan E, Chakravarti A, Gesteland R, Walters L. New goals for the U.S. Human Genome Project: 1998–2003. Science. 1998; 282: 682–9.

    Article  PubMed  CAS  Google Scholar 

  12. Waterston R, Sulston JE. The human genome project: reaching the finish line. Science. 1998; 282: 53–54.

    Article  PubMed  CAS  Google Scholar 

  13. Anderson WF, Field C, Venter JC. Mammalian gene studies: editorial overview. Curr Opin Biotechnol. 1994; 5: 577–8.

    Article  CAS  Google Scholar 

  14. Harris TJ, Rosen CA. Editorial overview: genetics, genomics and drug discovery. Curr Opin Biotechnol. 1994; 5: 637–8.

    Article  CAS  Google Scholar 

  15. Murray-Rust P. Bioinformatics and drug discovery. Curr Opin Biotechnol. 1994; 5: 648–53.

    Article  PubMed  CAS  Google Scholar 

  16. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990; 61: 759–67.

    Article  PubMed  CAS  Google Scholar 

  17. Zhang L, Zhou W, Velculescu VE, et al. Gene expression profiles in normal and cancer cells. Science. 1997; 276: 1268–72.

    Article  PubMed  CAS  Google Scholar 

  18. Hacia JG. Resequencing and mutational analysis using oligonucleotide microarrays. Nat. Genet. 1999; 21: 42–47.

    Article  PubMed  CAS  Google Scholar 

  19. Drews J. Genomic sciences and the medicine of tomorrow. Nat Biotechnol. 1996; 14: 1516–18.

    Article  PubMed  CAS  Google Scholar 

  20. Workman P. The potential for molecular oncology to define new drug targets. In: New Molecular Targets for Cancer Chemotherapy ( Kerr DJ, Workman P, eds.), CRC Press, Boca Raton, FL, 1994, p. 1.

    Google Scholar 

  21. Gibbs JB, Oliff A. Pharmaceutical research in molecular oncology. Cell. 1994; 79: 193–8.

    Article  PubMed  CAS  Google Scholar 

  22. Oliff A, Gibbs JB, McCormick F. New molecular targets for cancer therapy. Sci Am. 1996; September: 110–5.

    Google Scholar 

  23. Marshall CJ. Opportunities for pharmacological intervention in the ras pathway. Ann Oncol. 1995; 6 (Suppl 1): S63–S67.

    Article  Google Scholar 

  24. Lerner EC, Hamilton AD, Sebti SM. Inhibition of Ras prenylation: a signaling target for novel anti-cancer drug design. Anticancer Drug Des. 1997; 12: 229–38.

    PubMed  CAS  Google Scholar 

  25. Terrett NK, Gardner M, Gordon DW, Kobylecki RJ, Steele J. Combinatorial synthesis— the design of compound libraries and their application to drug discovery. Tetrahedron. 1995; 51: 8135–73.

    Article  CAS  Google Scholar 

  26. Bevan P, Ryder H, Shaw I. Identifying small-molecule lead compounds: the screening approach to drug discovery. Trends in Biotechnology. 1995; 13: 115–21.

    Article  PubMed  CAS  Google Scholar 

  27. Workman P. Towards intelligent anticancer drug screening in the post-genome era? Anticancer Drug Des. 1997; 12: 525–31.

    PubMed  CAS  Google Scholar 

  28. Blundell TL. Structure-based drug design. Nature. 1996; 384: 23–26.

    Article  PubMed  CAS  Google Scholar 

  29. Workman P. Pharmacokinetics and cancer: successes, failures and future prospects. Cancer Surv. 1993; 17: 1–26.

    PubMed  CAS  Google Scholar 

  30. Olah TV, McLoughlin DA, Gilbert JD. The simultaneous determination of mixtures of drug candidates by liquid chromatography/atmospheric pressure chemical ionization mass spectrometry as an in vivo drug screening procedure. Rapid Commun Mass Spectrom. 1997; 11: 17–23.

    Article  PubMed  CAS  Google Scholar 

  31. Brown JM, Workman P. Partition coefficient as a guide to the development of radiosensitizers which are less toxic than misonidazole. Radiat Res. 1990; 82: 171–90.

    Article  Google Scholar 

  32. Workman P, Brown JM. Structure–pharmacokinetic relationships for misonidazole analogues in mice. Cancer Chemother Pharmacol. 1981; 6: 39–49.

    Article  PubMed  CAS  Google Scholar 

  33. Mayer JM, van de Waterbeemd H. Development of quantitative structure–pharmacokinetic relationships. Environ Health Perspect. 1985; 61: 295–306.

    Article  PubMed  CAS  Google Scholar 

  34. Rowland M. Pharmacokinetics-QSAR: definitions, concepts, and models. In Quantitative Approaches to Drug Design ( Dearden JC, ed.), Elsevier, Amsterdam, 1983, pp. 155–61.

    Google Scholar 

  35. Rishton GM. Reactive compounds and in vitro false positives in HTS. Drug Discov Today. 1997; 2: 382.

    Article  CAS  Google Scholar 

  36. Current Drugs. Drug metabolism and pharmacokinetics symposium. ID weekly highlights Current Drugs Ltd, p. 25, September 1998.

    Google Scholar 

  37. Monks A, Scudiero DA, Johnson GS, Paull KD, Sausville EA. The NCI anti-cancer drug screen: a smart screen to identify effectors of novel targets. Anticancer Drug Des. 1997; 12: 533–41.

    PubMed  CAS  Google Scholar 

  38. Skelton LA, Ormerod MG, Titley J, Kimbell R, Brunton LA, Jackman AL. A novel class of lipophilic quinazoline-based folic acid analogues: cytotoxic agents with a folate-independent locus. Br J Cancer. 1999; 79: 1692–701.

    Article  PubMed  CAS  Google Scholar 

  39. Bradshaw TD, Wrigley S, Shi DF, Schultz RJ, Paull KD, Stevens MF. 2-(4-Aminophenyl) benzothiazoles: novel agents with selective profiles of in vitro anti-tumour activity. Br J Cancer. 1998; 77: 745–52.

    Article  PubMed  CAS  Google Scholar 

  40. Greengrass CW. Devising a research strategy. In: Medicinal Chemistry: Principles and Practice ( King FD, ed.), Royal Society of Chemistry, Cambridge, 1994, pp. 179–188.

    Google Scholar 

  41. Gura T. Systems for identifying new drugs are often faulty. Science. 1997; 278: 1041–2.

    Article  PubMed  CAS  Google Scholar 

  42. Burtles SS, Jodrell DI, Newell DR. Evaluation of “rodent only” preclinical toxicology for phase I trials of new cancer treatments—The Cancer Research Campaign (CRC) experience. Proc Amer Assoc Cancer Res. 1998; 39: 363.

    Google Scholar 

  43. Newlands ES, Stevens MF, Wedge SR, Wheelhouse RT, Brock C. Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev. 1997; 23: 35–61.

    Article  PubMed  CAS  Google Scholar 

  44. Graham MA, Kaye SB. New approaches in preclinical and clinical pharmacokinetics. Cancer Surv. 1993; 17: 27–49.

    PubMed  CAS  Google Scholar 

  45. Collins JM, Zaharko DS, Dedrick RL, Chabner BA. Potential roles for preclinical pharmacology in phase I clinical trials. Cancer Treat Rep. 1986; 70: 73–80.

    PubMed  CAS  Google Scholar 

  46. Graham MA, Workman P. The impact of pharmacokinetically guided dose escalation strategies in phase I clinical trials: clinical evaluation and recommendations for future studies. Ann Oncol. 1992; 3: 339–347.

    PubMed  CAS  Google Scholar 

  47. O’Quigley J, Pepe M, Fisher L. Continual reassessment method: a practical design for phase 1 clinical trials in cancer. Biometrics. 1990; 46: 33–48.

    Article  PubMed  Google Scholar 

  48. Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC. Accelerated titration designs for phase I clinical trials in oncology. JNatl CancerInst. 1997; 89: 1138–47.

    Article  CAS  Google Scholar 

  49. Maxwell RJ. New techniques in pharmacokinetic analysis of cancer drugs III: nuclear magnetic resonance. Cancer Surv. 1983; 17: 415–423.

    Google Scholar 

  50. Tilsley DW, Harte RJ, Jones T, et al. New techniques in the pharmacokinetic analysis of cancer drugs. IV. Positron emission tomography. Cancer Surv. 1993; 17: 425–42.

    PubMed  CAS  Google Scholar 

  51. Workman P, Maxwell RJ, Griffiths JR. Non-invasive MRS in new anticancer drug development. NMR Biomed. 1992; 5: 270–2.

    Article  PubMed  CAS  Google Scholar 

  52. Workman P. Bottlenecks in anticancer drug discovery and development: in vivo pharmacokinetic and pharmacodynamic issues and the potential role of PET. In: PETfor Drug Development and Evaluation ( Komar D, ed.), Kluwer, Dordrecht, 1995, p. 277.

    Chapter  Google Scholar 

  53. Workman P, Brunton VG, Robins DJ. Tyrosine kinase inhibitors. Semin Cancer Biol. 1992; 3: 369–81.

    PubMed  CAS  Google Scholar 

  54. Fry DW. Protein tyrosine kinases as therapeutic targets in cancer chemotherapy and recent advances in the development of new inhibitors. Exp Opin Invest Drugs. 1994; 3: 577–95.

    Article  CAS  Google Scholar 

  55. Levitzki A, Gazit A. Tyrosine kinase inhibition: an approach to drug development. Science. 1995; 267: 1782–8.

    Article  PubMed  CAS  Google Scholar 

  56. Patrick DR, Heimbrook PC. Protein kinase inhibitors for the treatment of cancer. Drug Discov Today. 1996; 1: 325–30.

    Article  CAS  Google Scholar 

  57. Strawn LM, Shawver LK. Tyrosine kinases in disease. Exp Opin Invest Drugs. 1998; 7: 553.

    Article  CAS  Google Scholar 

  58. Hunter T. A thousand and one protein kinases. Cell. 1987; 50: 823–9.

    Article  PubMed  CAS  Google Scholar 

  59. Hunter T. Oncoprotein networks. Cell. 1997; 88: 333–46.

    Article  PubMed  CAS  Google Scholar 

  60. Brunton VG, Carlin S, Workman P. Alterations in EGF-dependent proliferative and phosphorylation events in squamous cell carcinoma cell lines by a tyrosine kinase inhibitor. Anticancer Drug Des. 1994; 9: 311–29.

    PubMed  CAS  Google Scholar 

  61. McLeod HL, Brunton VG, Eckardt N, et al. In vivo pharmacology and anti-tumour evaluation of the tyrphostin tyrosine kinase inhibitor RG13022. Br J Cancer. 1996; 74: 1714–18.

    Article  PubMed  CAS  Google Scholar 

  62. Meydan N, Grunberger T, Dadi H, et al. Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature. 1996; 379: 645–8.

    Article  PubMed  CAS  Google Scholar 

  63. Mohammadi M, McMahon G, Sun L, et al. Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. Science. 1997; 276: 955–60.

    Article  PubMed  CAS  Google Scholar 

  64. Fry DW, Kraker AJ, McMichael A, et al. A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science. 1994; 265: 1093–5.

    Article  PubMed  CAS  Google Scholar 

  65. Ward WHJ, Cook PN, Slater AM, Davies DH, Holdgate GA, Green LR. Epidermal growth factor receptor tyrosine kinase. Biochem Pharmacol. 1994; 48: 659–66.

    Article  PubMed  CAS  Google Scholar 

  66. Wakeling AE, Barker AJ, Davies DH, et al. Specific inhibition of epidermal growth factor receptor tyrosine kinase by 4-anilinoquinazolines. Breast Cancer Res Treat. 1996; 38: 67–73.

    Article  PubMed  CAS  Google Scholar 

  67. Wakeling AE, Barker AJ, Davies DH, et al. New targets for therapeutic attack. Endocrin. Rel Cancer. 1997; 4: 351–5.

    Article  CAS  Google Scholar 

  68. Boyle FT, Costello GF. Cancer therapy: a move to the molecular level. Chem Soc Rev. 1998; 27: 251–61.

    Article  Google Scholar 

  69. Current Drugs. ZD-1839—an EGF receptor-tyrosine kinase inhibitor. ID weekly highlights Current Drugs Ltd, p. 45, April 1998.

    Google Scholar 

  70. Woodburn JR, Barker AJ, Gibson KH, et al. ZD 1839, an epidermal growth factor tyrosine kinase inhibitor selected for clinical development. Proc Am Assoc Cancer Res. 1997; 38: 633 (abstr.)

    Google Scholar 

  71. Kelly HC, Laight A, Morris CQ, Woodburn JR, Richmond GHP. Phase I data of ZD1839— an oral epidermal growth factor receptor tyrosine kinase inhibitor. Proceedings of the 10th International NCI Symposium in New Drugs in Cancer Therapy 1998; 109.

    Google Scholar 

  72. Iwata K, Miller PE, Barbacci EG, Arnold L, Doty J, DiOrio CI, Pustilnik LR, Reynolds M, Thelemann A, Sloan D, Moyer JD. CP-358,774: A selective EGFR kinase inhibitor with potent antiproliferative activity against HN5 head and neck tumor cells. Proc Am Assoc Cancer Res. 1997; 38: 633 (abstr.).

    Google Scholar 

  73. Senderowicz AM, Headlee D, Stinson SF, Lush RM, Kalil N, Villalba L, Hill K, Steinberg SM, Figg WD, Tompkins A, Arbuch SG, Sausville EA. Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms. J Clin Onc. 1998; 16: 2986–2999.

    CAS  Google Scholar 

  74. Gray NS, Wodicka L, Thunnissen AM, Morgan DO, Barnes G, LeClerc S, Meijer L, Kim S-H, Lockhart DJ, Schultz PG. Exploiting chemical libraries, structure and genomics in the search for kinase inhibitors. Science. 1998; 281: 533–8.

    Article  PubMed  CAS  Google Scholar 

  75. Shayesteh L, Lu Y, Baldocchi R, Godfrey T, Collins C, Pinkel D, Powell B, Mills GB, Gray JW. PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet. 1999; 21: 99–102.

    Article  PubMed  CAS  Google Scholar 

  76. Whitesell L, Mimnaugh EG, DeCosta B, Myers CE, Neckers LM. Inhibition of heat-shock protein HSP90-pp60v-src heteroprotein complex-formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci USA. 1994; 91: 8324–8.

    Article  PubMed  CAS  Google Scholar 

  77. Prodromou C, Roe SM, O’Brien R, Ladbury JE, Piper PW, Pearl LH. Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell. 1997; 90: 65–75.

    Article  PubMed  CAS  Google Scholar 

  78. Schulte TW, Neckers LM. The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important biologic activities with geldanamycin. Cancer Chemother Pharmacol. 1998; 42: 273–9.

    Article  PubMed  CAS  Google Scholar 

  79. Egorin MJ, Rosen DM, Wolff JH, Callery PS, Musser SM, Eiseman JL. Metabolism of 17-(allylamino)-17-demethoxygeldanamycin (NSC 330507) by murine and human hepatic preparations. Cancer Res. 1998; 58: 2385–96.

    PubMed  CAS  Google Scholar 

  80. Scrip No 2374 September 30th, p. 20 1998.

    Google Scholar 

  81. Page MJ, Amess B, Rohlff C, Stubberfield C, Parekh R. Proteomics: a major new technology for the drug discovery process. Drug Discov Today. 1999; 4: 55–62.

    Article  PubMed  CAS  Google Scholar 

  82. Workman P. Cell proliferation, cell cycle and apoptosis targets for cancer drug discovery: Strategies, strengths and pitfalls. In: Apoptosis and Cell Cycle Control. Basic Mechanisms and Implications for Treating Malignant Disease. Bios, Oxford, 1996, p. 205.

    Google Scholar 

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Authors
  1. Paul Workman
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Editors and Affiliations

  1. Hospital General of Granollers, Barcelona, Spain

    Miguel H. Bronchud MD, PhD

  2. Amgen Inc., Thousand Oaks, CA, USA

    Mary Ann Foote PhD  & Murray O. Robinson MD, PhD  & 

  3. Barbara Ann Karmonos Cancer Institute, The Detroit Medical Center, Wayne State University, Detroit, MI, USA

    William P. Peters PhD

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Workman, P. (2000). Emerging Molecular Therapies. In: Bronchud, M.H., Foote, M.A., Peters, W.P., Robinson, M.O. (eds) Principles of Molecular Oncology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-222-7_17

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  • DOI: https://doi.org/10.1007/978-1-59259-222-7_17

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-4757-6274-7

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