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  • Review Article
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Non-kinase targets of protein kinase inhibitors

Nature Reviews Drug Discovery volume 16, pages 424–440 (2017)Cite this article

Subjects

Key Points

  • Kinase targets and overall toxicity-related off-targets of kinase inhibitors are usually identified in the early stages of drug development. The kinase selectivity profiles are well documented in the literature.

  • Non-kinase targets of kinase inhibitors often remain undiscovered, as the cytotoxicity of the kinase inhibitor is attributed to the inhibition of the targeted kinase. This can lead to misinterpretation of data and faulty links between the pathway and disease pathology.

  • The phenomenon that kinase inhibitors exert their anticancer effect through unintended non-kinase targets is increasingly being appreciated, and it implies that the mechanism of action of kinase inhibitors should be investigated beyond the kinome.

  • Tubulin and bromodomain and extra-terminal domain (BET) proteins have so far been the most frequent non-kinase targets identified for a relatively large number of kinase inhibitors.

  • Detailed orthogonal approaches to drug–target validation using orthogonal inhibitors are needed for pharmacological investigations, in particular when working with kinase inhibitors. These approaches will generate more reliable and reproducible data.

  • It is anticipated that future research will uncover more novel non-kinase targets of kinase inhibitors, which will enable new discoveries and better-validated drug targets.

Abstract

Kinome-wide profiling platforms have comprehensively identified the relevant kinases that are targeted by numerous protein kinase inhibitors. However, recent projects have begun to discover non-kinase targets of kinase inhibitors. These non-kinase targets can contribute to the desired or undesired activities of inhibitors, or act as silent bystanders. As a full awareness of a drug's mechanism of action is crucial for the interpretation of results and for successful preclinical and clinical drug development, these discoveries highlight the importance of understanding the pharmacology of kinase inhibitors beyond the kinome. In this Review, I discuss kinase inhibitors for which non-kinase targets have been identified and the application of emerging techniques to validate drug–target engagement in intact cells.

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Figure 1: Identification of tivantinib as a tubulin-targeting drug.
Figure 2: Kinase and scaffolding functions of EGFR.
Figure 3: Kinase and scaffolding functions of RIPK1 and RIPK3.

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Acknowledgements

L.M. is a Cancer Institute New South Wales (NSW) Career Development Fellow supported by the National Health and Medical Research Council (NHMRC Project grant APP1106145), the Cancer Institute NSW (Grant reference: 15/CDF/1-07), the National Foundation for Medical Research and Innovation (NFMRI), The University of Sydney, the Brain Foundation Australia and the Sydney Medical School Foundation. The author thanks J. Silke for critical revision of the Review.

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    Lenka Munoz

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Km (ATP)

The concentration of ATP that permits the kinase to achieve half the maximum rate of reaction (Vmax). Higher Km (ATP) values indicate a lower affinity of the kinase for ATP.

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Munoz, L. Non-kinase targets of protein kinase inhibitors. Nat Rev Drug Discov 16, 424–440 (2017). https://doi.org/10.1038/nrd.2016.266

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