Inducing Folding By Crating the Target

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Abstract

Kinases may be exploited as anticancer drug targets but their conformational plasticity often hinders the success of structure-based design. This is because of structural adaptation: target structures may change or proteins may adopt new conformations upon association with the ligand in unexpected and unpredictable ways. This may be the main reason for the modest interest in rational drug design when targeting regions with high disorder propensity such as the activation loop of a protein kinase. Yet this region presents the largest amino acid variability within the family and thus constitutes an attractive target to control specificity. In this chapter we advocate for a strategy to target flexible regions, offering a way to control the induced folding and turn it into a selectivity-promoting feature.

Keywords

Chronic Myeloid Leukemia Activation Loop Packing Defect Flexible Region Folding Problem 
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.
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References

  1. 1.
    Dancey J, Sausville EA (2003) Issues and progress with protein kinase inhibitors for cancer treatment. Nat Rev Drug Discov 2:296–313CrossRefGoogle Scholar
  2. 2.
    Tibes R, Trent J, Kurzrock R (2005) Tyrosine kinase inhibitors and the dawn of molecular cancer therapeutics. Annu Rev Pharmacol Toxicol 45:357–384CrossRefGoogle Scholar
  3. 3.
    Schindler T, Bornmann W, Pellicena P et al (2000) Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 289:1938–1942CrossRefGoogle Scholar
  4. 4.
    Schiffer CA (2007) BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia. N Engl J Med 357:258–265CrossRefGoogle Scholar
  5. 5.
    Crespo A, Fernández A (2007) Kinase packing defects as drug targets. Drug Discov Today 12:917–923Google Scholar
  6. 6.
    Teague S (2003) Implications of protein flexibility for drug discovery. Nat Rev Drug Discov 2:527–541CrossRefGoogle Scholar
  7. 7.
    Damm KL, Carlson HA (2007) Exploring experimental sources of multiple protein conformations in structure-based drug design. J Am Chem Soc 129:8225–8235CrossRefGoogle Scholar
  8. 8.
    Hornak V, Simmerling C (2007) Targeting structural flexibility in HIV-1 protease inhibitor binding. Drug Discov Today 12:132–138CrossRefGoogle Scholar
  9. 9.
    Erickson J (2004) Lessons in molecular recognition: The effects of ligand and protein flexibility on molecular docking accuracy. J Med Chem 47:45–55CrossRefGoogle Scholar
  10. 10.
    Noble ME, Endicott JA, Johnson LN (2004) Protein kinase inhibitors: Insights into drug design from structure. Science 303:1800–1805CrossRefGoogle Scholar
  11. 11.
    Pietrosemoli N, Crespo A, Fernández A (2007) Dehydration propensity of order-disorder intermediate regions in soluble proteins. J Proteome Res 6:3519–3526CrossRefGoogle Scholar
  12. 12.
    Chen J, Zhang X, Fernández A (2007) Molecular basis for specificity in the druggable kinome: Sequence-based analysis. Bioinformatics 23:563–572CrossRefGoogle Scholar
  13. 13.
    Fernández A (2004) Keeping dry and crossing membranes. Nat Biotechnol 22:1081–1084CrossRefGoogle Scholar
  14. 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 117:4044–4054CrossRefGoogle Scholar
  15. 15.
    Crunkhorn S (2008) Anticancer drugs: Redesigning kinase inhibitors. Nat Rev Drug Discov 7:120–121Google Scholar
  16. 16.
    Fernández A, Sanguino A, Peng Z et al (2007) Rational drug redesign to overcome drug resistance in cancer therapy: Imatinib moving target. Cancer Res 67:4028–4033CrossRefGoogle Scholar
  17. 17.
    Demetri GD, von Mehren M, Blanke CD et al (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472–480CrossRefGoogle Scholar
  18. 18.
    Kerkela R, Grazette L, Yacobi R et al (2006) Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 12:908–916CrossRefGoogle Scholar
  19. 19.
    Force T, Krause D, van Etten RA (2007) Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 7:332–344CrossRefGoogle Scholar
  20. 20.
    Demetri GD (2007) Structural reengineering of imatinib to decrease cardiac risk in cancer therapy. J Clin Invest 117:3650–3653CrossRefGoogle Scholar
  21. 21.
    Fernández A, Bazan S, Chen J (2009) Taming the induced folding of drug-targeted kinases. Trends Pharmacol Sci 30: 66–71CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Department of BioengineeringRice UniversityHoustonUSA

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