Protein phosphorylation lies at the heart of cell signalling, and somatic mutation(s) in kinases drives and sustains a multitude of human diseases, including cancer. The human protein kinase superfamily (the kinome) encodes approximately 50 ‘pseudokinases’, which were initially predicted to be incapable of dynamic cell signalling when compared with canonical enzymatically active kinases. This assumption was supported by bioinformatics, which showed that amino acid changes at one or more key loci, making up the nucleotide-binding site or phosphotransferase machinery, were conserved in multiple vertebrate and non-vertebrate pseudokinase homologues. Protein kinases are highly attractive targets for drug discovery, as evidenced by the approval of almost 30 kinase inhibitors in oncology, and the successful development of the dual JAK1/2 (Janus kinase 1/2) inhibitor ruxolitinib for inflammatory indications. However, for such a large (>550) protein family, a remarkable number have still not been analysed at the molecular level, and only a surprisingly small percentage of kinases have been successfully targeted clinically. This is despite evidence that many are potential candidates for the development of new therapeutics. Indeed, several recent reports confirm that disease-associated pseudokinases can bind to nucleotide co-factors at concentrations achievable in the cell. Together, these findings suggest that drug targeting using either ATP-site or unbiased ligand-discovery approaches should now be attempted using the validation technology currently employed to evaluate their classic protein kinase counterparts. In the present review, we discuss members of the human pseudokinome repertoire, and catalogue somatic amino acid pseudokinase mutations that are emerging as the depth and clinical coverage of the human cancer pseudokinome expand.
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January 2015
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Review Article|
January 06 2015
Going for broke: targeting the human cancer pseudokinome1
Fiona P. Bailey;
Fiona P. Bailey
*Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, L69 7ZB UK
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Dominic P. Byrne;
Dominic P. Byrne
*Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, L69 7ZB UK
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Daniel McSkimming;
Daniel McSkimming
†Institute of Bioinformatics, University of Georgia, Athens, GA 30602 U.S.A.
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Natarajan Kannan;
Natarajan Kannan
†Institute of Bioinformatics, University of Georgia, Athens, GA 30602 U.S.A.
‡Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602 U.S.A.
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Patrick A. Eyers
Patrick A. Eyers
2
*Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, L69 7ZB UK
2To whom correspondence should be addressed (email Patrick.eyers@liverpool.ac.uk).
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Publisher: Portland Press Ltd
Received:
August 14 2014
Revision Received:
October 14 2014
Accepted:
October 29 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2015 Biochemical Society
2015
Biochem J (2015) 465 (2): 195–211.
Article history
Received:
August 14 2014
Revision Received:
October 14 2014
Accepted:
October 29 2014
Connected Content
A correction has been published:
2) Going for broke: targeting the human cancer pseudokinome
Citation
Fiona P. Bailey, Dominic P. Byrne, Daniel McSkimming, Natarajan Kannan, Patrick A. Eyers; Going for broke: targeting the human cancer pseudokinome. Biochem J 15 January 2015; 465 (2): 195–211. doi: https://doi.org/10.1042/BJ20141060
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