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Re-engineering an Anticancer Drug to Make It Safer: Modifying Imatinib to Curb Its Side Effects

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Transformative Concepts for Drug Design: Target Wrapping
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Abstract

As indicated in the previous chapter, molecular therapeutic approaches to cancer are often geared at interfering with signaling pathways that govern cell fate or proliferation. These strategies target kinases, the quintessential signal transducers in the cell. This approach remains challenging because kinases are evolutionarily and therefore structurally related and thus kinase inhibitors often lack specificity or possess uncontrolled cross-reactivities, which may lead to toxic side effects. This chapter illustrates the power of the wrapping concept in developing safer kinase inhibitors, thus unraveling a rational approach to fulfill this therapeutic imperative. The focus of this chapter is the redesign of the anticancer drug imatinib (Gleevec) used to treat chronic myeloid leukemia, where its primary target is the chimeric Bcr-Abl kinase, as well as certain solid tumors based on its impact on the C-Kit kinase.

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References

  1. Dancey J, Sausville EA (2003) Issues and progress with protein kinase inhibitors for cancer treatment. Nat Rev Drug Discov 2:296–313

    Article  Google Scholar 

  2. Levitski A, Gazit A (1995) Tyrosine kinase inhibition: An approach to drug development. Science 267:1782–1788

    Article  Google Scholar 

  3. Tibes R, Trent J, Kurzrock R (2005) Tyrosine kinase inhibitors and the dawn of molecular cancer therapeutics. Annu Rev Pharmacol Toxicol 45:357–84

    Article  Google Scholar 

  4. Gibbs J, Oliff A (1994) Pharmaceutical research in molecular oncology. Cell 79:193–198

    Article  Google Scholar 

  5. Donato NJ, Talpaz M (2000) Clinical use of tyrosine kinase inhibitors: Therapy for chronic myelogenous leukemia and other cancers. Clin Cancer Res 6:2965–2966

    Google Scholar 

  6. Fabian MA, Biggs WH, Treiber DK et al (2005) A small molecule kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 23:329–336

    Article  Google Scholar 

  7. Gambacorti-Passerini C, le Coutre P, Mologni L et al (1997) Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis. Blood Cells Mol Dis 23:380–394

    Article  Google Scholar 

  8. Schindler T, Bornmann W, Pellicena P et al (2000) Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 289:1938–1942

    Article  Google Scholar 

  9. Attoub S, Rivat C, Rodrigues S et al (2002) The C-kit tyrosine kinase inhibitor STI-571 for colorectal cancer therapy. Cancer Res 62:4879–4883

    Google Scholar 

  10. DeMatteo RP (2002) The GIST of targeted cancer therapy: A tumor (gastrointestinal stromal tumor), a mutated gene (c-kit), and a molecular inhibitor (STI571). Ann Surg Oncol 9:831–839

    Article  Google Scholar 

  11. Skene RJ, Kraus ML, Scheibe DN et al (2004) Structural basis for autoinhibition and STI-571 inhibition of C-kit tyrosine kinase. J Biol Chem 279:31655–31663

    Article  Google Scholar 

  12. Tuveson DA, Willis NA, Jacks T et al (2001) STI571 inactivation of the gastrointestinal stromal tumor C-kit oncoprotein: Biological and clinical implications. Oncogene 20:5054–5058

    Article  Google Scholar 

  13. Chen JP, Zhang X, Fernández A (2007) Molecular basis for specificity in the druggable kinome: Sequence-based analysis. Bioinformatics 23:563–572

    Article  Google Scholar 

  14. Fernández A, Sanguino A, Peng Z et al (2007) An anticancer C-kit kinase inhibitor is re-engineered to make it more active and less cardiotoxic. J Clin Invest 117:4044–4054

    Article  Google Scholar 

  15. Kerkela R, Grazette L, Yacobi R et al (2006) Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 12:908–916

    Article  Google Scholar 

  16. Druker BJ (2004) Molecularly targeted therapy: Have the floodgates opened? Oncologist 9:357–360

    Article  Google Scholar 

  17. Fernández A, Scheraga HA (2003) Insufficiently dehydrated hydrogen bonds as determinants of protein interactions. Proc Natl Acad Sci USA 100:113–118

    Article  Google Scholar 

  18. Barker S, Kassel D, Weigl D et al (1995) Characterization of pp60c-src tyrosine kinase activities using a continuous assay: Autoactivation of the enzyme is an intermolecular autophosphorylation process. Biochemistry 34:14843–14851

    Article  Google Scholar 

  19. Songyang Z, Carraway KL, Eck M et al (1995) Catalytic specificity of protein-tyrosine kinases is critical for selective signalling. Nature 373:536–539

    Article  Google Scholar 

  20. Clarkson B, Strife A, Wisniewski D, Lambek CL, Liu C (2003) Chronic myelogenous leukemia as a paradigm of early cancer and possible curative strategy. Leukemia 17:1211–1262

    Article  Google Scholar 

  21. Prenen H, Deroose C, Vermaelen P, Sciot R, Debiec-Rychter M (2006) Establishment of a mouse gastrointestinal stromal tumour model and evaluation of response to Imatinib by small animal positron emission tomography. Anticancer Res 26:1247–1252

    Google Scholar 

  22. Baines CP, Molkentin JD (2005) Stress signaling pathways that modulate cardiac myocyte apoptosis. J Mol Cell Cardiol 38:47–62

    Article  Google Scholar 

  23. Scheuermann-Freestone M, Simon Freestone N, Langenickel T et al (2001) A new model of congestive heart failure in the mouse due to chronic volume overload. Eur J Heart Fail 3:535–543

    Article  Google Scholar 

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Correspondence to Ariel Fernandez .

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Fernandez, A. (2010). Re-engineering an Anticancer Drug to Make It Safer: Modifying Imatinib to Curb Its Side Effects. In: Transformative Concepts for Drug Design: Target Wrapping. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-11792-3_8

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  • DOI: https://doi.org/10.1007/978-3-642-11792-3_8

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  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-11791-6

  • Online ISBN: 978-3-642-11792-3

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