The specificities of 65 compounds reported to be relatively specific inhibitors of protein kinases have been profiled against a panel of 70–80 protein kinases. On the basis of this information, the effects of compounds that we have studied in cells and other data in the literature, we recommend the use of the following small-molecule inhibitors: SB 203580/SB202190 and BIRB 0796 to be used in parallel to assess the physiological roles of p38 MAPK (mitogen-activated protein kinase) isoforms, PI-103 and wortmannin to be used in parallel to inhibit phosphatidylinositol (phosphoinositide) 3-kinases, PP1 or PP2 to be used in parallel with Src-I1 (Src inhibitor-1) to inhibit Src family members; PD 184352 or PD 0325901 to inhibit MKK1 (MAPK kinase-1) or MKK1 plus MKK5, Akt-I-1/2 to inhibit the activation of PKB (protein kinase B/Akt), rapamycin to inhibit TORC1 [mTOR (mammalian target of rapamycin)–raptor (regulatory associated protein of mTOR) complex], CT 99021 to inhibit GSK3 (glycogen synthase kinase 3), BI-D1870 and SL0101 or FMK (fluoromethylketone) to be used in parallel to inhibit RSK (ribosomal S6 kinase), D4476 to inhibit CK1 (casein kinase 1), VX680 to inhibit Aurora kinases, and roscovitine as a pan-CDK (cyclin-dependent kinase) inhibitor. We have also identified harmine as a potent and specific inhibitor of DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) in vitro. The results have further emphasized the need for considerable caution in using small-molecule inhibitors of protein kinases to assess the physiological roles of these enzymes. Despite being used widely, many of the compounds that we analysed were too non-specific for useful conclusions to be made, other than to exclude the involvement of particular protein kinases in cellular processes.
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December 2007
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Research Article|
November 28 2007
The selectivity of protein kinase inhibitors: a further update
Jenny Bain;
Jenny Bain
1
*Division of Signal Transduction Therapy, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Lorna Plater;
Lorna Plater
1
*Division of Signal Transduction Therapy, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Matt Elliott;
Matt Elliott
1
*Division of Signal Transduction Therapy, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Natalia Shpiro;
Natalia Shpiro
1
†MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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C. James Hastie;
C. James Hastie
*Division of Signal Transduction Therapy, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Hilary Mclauchlan;
Hilary Mclauchlan
*Division of Signal Transduction Therapy, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Iva Klevernic;
Iva Klevernic
†MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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J. Simon C. Arthur;
J. Simon C. Arthur
†MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Dario R. Alessi;
Dario R. Alessi
†MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Philip Cohen
Philip Cohen
2
*Division of Signal Transduction Therapy, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
†MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
2To whom correspondence should be addressed (email p.cohen@dundee.ac.uk).
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Publisher: Portland Press Ltd
Received:
June 14 2007
Revision Received:
August 28 2007
Accepted:
September 06 2007
Accepted Manuscript online:
September 13 2007
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2007 Biochemical Society
2007
Biochem J (2007) 408 (3): 297–315.
Article history
Received:
June 14 2007
Revision Received:
August 28 2007
Accepted:
September 06 2007
Accepted Manuscript online:
September 13 2007
Citation
Jenny Bain, Lorna Plater, Matt Elliott, Natalia Shpiro, C. James Hastie, Hilary Mclauchlan, Iva Klevernic, J. Simon C. Arthur, Dario R. Alessi, Philip Cohen; The selectivity of protein kinase inhibitors: a further update. Biochem J 15 December 2007; 408 (3): 297–315. doi: https://doi.org/10.1042/BJ20070797
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