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The ins and outs of selective kinase inhibitor development

Protein kinases have emerged as one of the most successful families of drug targets. To date, most selective kinase inhibitors have been discovered serendipitously either through broad selectivity screening or through the discovery of unique binding modes. Here we discuss design strategies that could lead to a broader coverage of the kinome with selective inhibitors and to a more rational approach for developing them.

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Figure 1: Milestones in kinase drug and inhibitor discovery.
Figure 2: Canonical kinase inhibitor binding modes and examples of selective inhibitors.

References

  1. Knighton, D.R. et al. Science 253, 414–420 (1991).

    Article  CAS  Google Scholar 

  2. Fedorov, O., Muller, S. & Knapp, S. Nat. Chem. Biol. 6, 166–169 (2010).

    Article  CAS  Google Scholar 

  3. Knapp, S. & Sundstrom, M. Curr. Opin. Pharmacol. 17, 58–63 (2014).

    Article  CAS  Google Scholar 

  4. Yang, J. et al. Chem. Biol. 18, 177–186 (2011).

    Article  CAS  Google Scholar 

  5. Fabian, M.A. et al. Nat. Biotechnol. 23, 329–336 (2005).

    Article  CAS  Google Scholar 

  6. Bantscheff, M. et al. Nat. Biotechnol. 25, 1035–1044 (2007).

    Article  CAS  Google Scholar 

  7. Davis, M.I. et al. Nat. Biotechnol. 29, 1046–1051 (2011).

    Article  CAS  Google Scholar 

  8. Zhao, Z. et al. ACS Chem. Biol. 9, 1230–1241 (2014).

    Article  CAS  Google Scholar 

  9. Debreczeni, J.E. et al. Angew. Chem. Int. Edn. Engl. 45, 1580–1585 (2006).

    Article  CAS  Google Scholar 

  10. Koeberle, S.C. et al. Nat. Chem. Biol. 8, 141–143 (2012).

    Article  CAS  Google Scholar 

  11. Gammons, M.V. et al. Invest. Ophthalmol. Vis. Sci. 54, 6052–6062 (2013).

    Article  CAS  Google Scholar 

  12. Liu, Q. et al. Chem. Biol. 20, 146–159 (2013).

    Article  Google Scholar 

  13. Woyach, J.A. et al. N. Engl. J. Med. 370, 2286–2294 (2014).

    Article  Google Scholar 

  14. Schindler, T. et al. Science 289, 1938–1942 (2000).

    Article  CAS  Google Scholar 

  15. Pike, A.C. et al. EMBO J. 27, 704–714 (2008).

    Article  CAS  Google Scholar 

  16. Hill, Z.B., Perera, B.G., Andrews, S.S. & Maly, D.J. ACS Chem. Biol. 7, 487–495 (2012).

    Article  CAS  Google Scholar 

  17. Axten, J.M. et al. J. Med. Chem. 55, 7193–7207 (2012).

    Article  CAS  Google Scholar 

  18. Wood, E.R. et al. Cancer Res. 64, 6652–6659 (2004).

    Article  CAS  Google Scholar 

  19. Di Paolo, J.A. et al. Nat. Chem. Biol. 7, 41–50 (2011).

    Article  CAS  Google Scholar 

  20. Guimarães, C.R. et al. J. Chem. Inf. Model. 51, 1199–1204 (2011).

    Article  Google Scholar 

  21. Chaikuad, A. et al. Nat. Chem. Biol. 10, 853–860 (2014).

    Article  CAS  Google Scholar 

  22. Zhang, J. et al. Nature 463, 501–506 (2010).

    Article  CAS  Google Scholar 

  23. Hindie, V. et al. Nat. Chem. Biol. 5, 758–764 (2009).

    Article  CAS  Google Scholar 

  24. Yap, T.A. et al. J. Clin. Oncol. 29, 4688–4695 (2011).

    Article  CAS  Google Scholar 

  25. Ciceri, P. et al. Nat. Chem. Biol. 10, 305–312 (2014).

    Article  CAS  Google Scholar 

Download references

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Correspondence to Nathanael S Gray or Stefan Knapp.

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Müller, S., Chaikuad, A., Gray, N. et al. The ins and outs of selective kinase inhibitor development. Nat Chem Biol 11, 818–821 (2015). https://doi.org/10.1038/nchembio.1938

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