Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research
  • Published:

A quantitative analysis of kinase inhibitor selectivity

Nature Biotechnology volume 26, pages 127–132 (2008)Cite this article

Abstract

Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets1,2. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome2,3,4. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Small molecule–kinase interaction maps for 38 kinase inhibitors.
Figure 2: Selectivity scores as a quantitative measure of specificity.
Figure 3: The effect of panel size on apparent selectivity.

Similar content being viewed by others

References

  1. Baselga, J. Targeting tyrosine kinases in cancer: the second wave. Science 312, 1175–1178 (2006).

    Article  CAS  Google Scholar 

  2. Sebolt-Leopold, J.S. & English, J.M. Mechanisms of drug inhibition of signalling molecules. Nature 441, 457–462 (2006).

    Article  CAS  Google Scholar 

  3. Garber, K. The second wave in kinase cancer drugs. Nat. Biotechnol. 24, 127–130 (2006).

    Article  CAS  Google Scholar 

  4. Knight, Z.A. & Shokat, K.M. Features of selective kinase inhibitors. Chem. Biol. 12, 621–637 (2005).

    Article  CAS  Google Scholar 

  5. Bain, J., McLauchlan, H., Elliott, M. & Cohen, P. The specificities of protein kinase inhibitors: an update. Biochem. J. 371, 199–204 (2003).

    Article  CAS  Google Scholar 

  6. Fabian, M.A. et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat. Biotechnol. 23, 329–336 (2005).

    Article  CAS  Google Scholar 

  7. Manning, G., Whyte, D.B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912–1934 (2002).

    Article  CAS  Google Scholar 

  8. Carter, T.A. et al. Inhibition of drug-resistant mutants of ABL, KIT and EGFR Kinases. Proc. Natl. Acad. Sci. USA 102, 11011–11016 (2005).

    Article  CAS  Google Scholar 

  9. Wood, E.R. et al. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res. 64, 6652–6659 (2004).

    Article  CAS  Google Scholar 

  10. Lombardo, L.J. et al. Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J. Med. Chem. 47, 6658–6661 (2004).

    Article  CAS  Google Scholar 

  11. Sun, L. et al. Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J. Med. Chem. 46, 1116–1119 (2003).

    Article  CAS  Google Scholar 

  12. Lowinger, T.B., Riedl, B., Dumas, J. & Smith, R.A. Design and discovery of small molecules targeting raf-1 kinase. Curr. Pharm. Des. 8, 2269–2278 (2002).

    Article  CAS  Google Scholar 

  13. Escudier, B. et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med. 356, 125–134 (2007).

    Article  CAS  Google Scholar 

  14. Flaherty, K.T. Sorafenib in renal cell carcinoma. Clin. Cancer Res. 13, 747s–752s (2007).

    Article  CAS  Google Scholar 

  15. Wilhelm, S.M. et al. BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 64, 7099–7109 (2004).

    Article  CAS  Google Scholar 

  16. Buchdunger, E. et al. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J. Pharmacol. Exp. Ther. 295, 139–145 (2000).

    CAS  PubMed  Google Scholar 

  17. Heinrich, M.C. et al. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 96, 925–932 (2000).

    CAS  PubMed  Google Scholar 

  18. Joensuu, H. et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N. Engl. J. Med. 344, 1052–1056 (2001).

    Article  CAS  Google Scholar 

  19. Giles, F.J. et al. MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Blood 109, 500–502 (2007).

    Article  CAS  Google Scholar 

  20. Chen, J., Zhang, X. & Fernandez, A. Molecular basis for specificity in the druggable kinome: sequence-based analysis. Bioinformatics 23, 563–572 (2007).

    Article  CAS  Google Scholar 

  21. Ohren, J.F. et al. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat. Struct. Mol. Biol. 11, 1192–1197 (2004).

    Article  CAS  Google Scholar 

  22. Cuenda, A. et al. SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Lett. 364, 229–233 (1995).

    Article  CAS  Google Scholar 

  23. Morin, M.J. From oncogene to drug: development of small molecule tyrosine kinase inhibitors as anti-tumor and anti-angiogenic agents. Oncogene 19, 6574–6583 (2000).

    Article  CAS  Google Scholar 

  24. Sako, T., Tauber, A.I., Jeng, A.Y., Yuspa, S.H. & Blumberg, P.M. Contrasting actions of staurosporine, a protein kinase C inhibitor, on human neutrophils and primary mouse epidermal cells. Cancer Res. 48, 4646–4650 (1988).

    CAS  PubMed  Google Scholar 

  25. Vieth, M. et al. Kinomics-structural biology and chemogenomics of kinase inhibitors and targets. Biochim. Biophys. Acta 1697, 243–257 (2004).

    Article  CAS  Google Scholar 

  26. Allen, L.F., Lenehan, P.F., Eiseman, I.A., Elliott, W.L. & Fry, D.W. Potential benefits of the irreversible pan-erbB inhibitor, CI-1033, in the treatment of breast cancer. Semin. Oncol. 29, 11–21 (2002).

    Article  CAS  Google Scholar 

  27. Jirousek, M.R. et al. (S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16, 21-dimetheno-1H, 13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-d ione (LY333531) and related analogues: isozyme selective inhibitors of protein kinase C beta. J. Med. Chem. 39, 2664–2671 (1996).

    Article  CAS  Google Scholar 

  28. Trudel, S. et al. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood 105, 2941–2948 (2005).

    Article  CAS  Google Scholar 

  29. Bach, S. et al. Roscovitine targets, protein kinases and pyridoxal kinase. J. Biol. Chem. 280, 31208–31219 (2005).

    Article  CAS  Google Scholar 

  30. Bantscheff, M. et al. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat. Biotechnol. 25, 1035–1044 (2007).

    Article  CAS  Google Scholar 

  31. Melnick, J.S. et al. An efficient rapid system for profiling the cellular activities of molecular libraries. Proc. Natl. Acad. Sci. USA 103, 3153–3158 (2006).

    Article  CAS  Google Scholar 

  32. Sheinerman, F.B., Giraud, E. & Laoui, A. High affinity targets of protein kinase inhibitors have similar residues at the positions energetically important for binding. J. Mol. Biol. 352, 1134–1156 (2005).

    Article  CAS  Google Scholar 

  33. Graczyk, P.P. Gini coefficient: a new way to express selectivity of kinase inhibitors against a family of kinases. J. Med. Chem. 50, 5773–5779 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Wendell Wierenga, Stephen Keane, Shripad Bhagwat and David O'Neill for critical reading of the manuscript, Richard Boult for writing software tools to facilitate data collection, processing and analysis, Antonio Torres, Jackie Swainson, Anne Lacorte, Brian Kinley, Lisa Ramos, Melissa Garren and Amber Van Sickle-Birch for expert technical assistance, Markus Herrgard for helpful discussions, and Bristol-Myers Squibb for providing dasatinib. The phylogenetic tree of the human kinome is reproduced with permission of Science and Cell Signaling Technology, Inc. (http://www.cellsignal.com/). With sponsorship by Cell Signaling Technology and Sugen, the figure was originally presented as a poster in Science to accompany the first analysis of the complete human kinome in a paper by Manning et al.7.

Author information

Author notes

  1. Stephanie Pritchard

    Present address: Present address: Tufts University School of Medicine, 136 Harrison Avenue, Boston, Massachusetts 02111, USA.,

  2. Mazen W Karaman, Sanna Herrgard, Daniel K Treiber and Paul Gallant: These authors contributed equally to this work.

Authors and Affiliations

  1. Ambit Biosciences, 4215 Sorrento Valley Blvd., San Diego, 92121, California, USA

    Mazen W Karaman, Sanna Herrgard, Daniel K Treiber, Paul Gallant, Corey E Atteridge, Brian T Campbell, Katrina W Chan, Pietro Ciceri, Mindy I Davis, Philip T Edeen, Raffaella Faraoni, Mark Floyd, Jeremy P Hunt, Daniel J Lockhart, Zdravko V Milanov, Michael J Morrison, Gabriel Pallares, Hitesh K Patel, Stephanie Pritchard, Lisa M Wodicka & Patrick P Zarrinkar

Authors
  1. Mazen W Karaman
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Sanna Herrgard
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Daniel K Treiber
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Paul Gallant
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Corey E Atteridge
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Brian T Campbell
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Katrina W Chan
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Pietro Ciceri
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Mindy I Davis
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Philip T Edeen
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Raffaella Faraoni
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Mark Floyd
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Jeremy P Hunt
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Daniel J Lockhart
    View author publications

    You can also search for this author inPubMed Google Scholar

  15. Zdravko V Milanov
    View author publications

    You can also search for this author inPubMed Google Scholar

  16. Michael J Morrison
    View author publications

    You can also search for this author inPubMed Google Scholar

  17. Gabriel Pallares
    View author publications

    You can also search for this author inPubMed Google Scholar

  18. Hitesh K Patel
    View author publications

    You can also search for this author inPubMed Google Scholar

  19. Stephanie Pritchard
    View author publications

    You can also search for this author inPubMed Google Scholar

  20. Lisa M Wodicka
    View author publications

    You can also search for this author inPubMed Google Scholar

  21. Patrick P Zarrinkar
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Patrick P Zarrinkar.

Ethics declarations

Competing interests

The authors declare competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/naturebiotechnology/.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1,2 and Supplementary Tables 1–5 (PDF 2009 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Karaman, M., Herrgard, S., Treiber, D. et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 26, 127–132 (2008). https://doi.org/10.1038/nbt1358

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nbt1358

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing