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A quantitative analysis of kinase inhibitor selectivity

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.

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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.

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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.

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Correspondence to Patrick P Zarrinkar.

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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

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