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Comprehensive analysis of kinase inhibitor selectivity

Abstract

We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.

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Figure 1: Quantitative distribution of kinome-wide selectivity of compounds.
Figure 2: Quantitative distribution of compound selectivity of kinases.
Figure 3: Selective inhibitors for primary targets.
Figure 4: Group-selective compounds.

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Acknowledgements

We thank W. Wierenga for critical reading of the manuscript, A. Torres, G. Riggs and M. Costa for compound management, M. Floyd and L. Ramos for expert molecular biology technical assistance, C. Shewmaker and J. Lowe for expert compound screening technical assistance, R. Faraoni for advice on compound synthesis and D. Jones for assistance preparing Figure 4.

Author information

Authors and Affiliations

Authors

Contributions

M.I.D. coordinated development of the assay panel, J.P.H. developed technology to enhance the efficiency of compound screening, S.H. analyzed data, M.I.D., J.P.H., P.C. and L.M.W. developed binding assay technology and performed assay development, G.P. coordinated and executed the measurement of Kd values, M.H. synthesized compounds, D.K.T. conceived the technology, designed assay development strategies, and supervised technology and assay development, S.H. and D.K.T. contributed to preparation of the manuscript, P.P.Z. designed the study, supervised the project, analyzed data and wrote the manuscript.

Corresponding authors

Correspondence to Daniel K Treiber or Patrick P Zarrinkar.

Ethics declarations

Competing interests

All authors are former or current employees of Ambit Biosciences and were employed by Ambit during the course of the project described in the manuscript. J.P.H., P.C., L.M.W., G.P. and D.K.T. are current employees of Discoverx Corp. Discoverx has acquired the technology used for the project from Ambit Biosciences.

Supplementary information

Supplementary Text and Figures

Supplementary Table 2 and Supplementary Figures 1–3 (PDF 2922 kb)

Supplementary Table 1

List of 442 kinase domains in the assay panel and their calculated kinase selectivity scores. (XLS 92 kb)

Supplementary Table 3

Compounds tested, their primary targets, and comparison of published and measured activities. (XLS 39 kb)

Supplementary Table 4

Binding results (Kd's in nM) for 72 inhibitors vs 442 kinase assays. Blank fields indicate combinations that were tested, but for which binding was weak (Kd > 10 uM), or not detected in a 10 uM primary screen. (XLS 297 kb)

Supplementary Table 5

Compound selectivity scores. (XLS 31 kb)

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Davis, M., Hunt, J., Herrgard, S. et al. Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol 29, 1046–1051 (2011). https://doi.org/10.1038/nbt.1990

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  • DOI: https://doi.org/10.1038/nbt.1990

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