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Lookup NU author(s): Elloise Stephenson, Professor Jonathan HigginsORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Protein kinases play vital roles in controlling cell behavior, and an array of kinase inhibitors are used successfully for treatment of disease. Typical drug development pipelines involve biological studies to validate a protein kinase target, followed by the identification of small molecules that effectively inhibit this target in cells, animal models, and patients. However, it is clear that protein kinases operate within complex signaling networks. These networks increase the resilience of signaling pathways, which can render cells relatively insensitive to inhibition of a single kinase, and provide the potential for pathway rewiring, which can result in resistance to therapy. It is therefore vital to understand the properties of kinase signaling networks in health and disease so that we can design effective multi-targeted drugs or combinations of drugs. Here, we outline how pharmacological and chemo-genetic approaches can contribute to such knowledge, despite the known low selectivity of many kinase inhibitors. We discuss how detailed profiling of target engagement by kinase inhibitors can underpin these studies; how chemical probes can be used to uncover kinase-substrate relationships, and how these tools can be used to gain insight into the configuration and function of kinase signaling networks.
Author(s): Stephenson EH, Higgins JMG
Publication type: Review
Publication status: Published
Journal: Frontiers in Pharmacology
Year: 2023
Volume: 14
Online publication date: 14/12/2023
Acceptance date: 27/11/2023
ISSN (electronic): 1663-9812
URL: https://doi.org/10.3389/fphar.2023.1310135
DOI: 10.3389/fphar.2023.1310135
