The selectivity of protein kinase inhibitors: a further update

Jenny Bain, Lorna Plater, Matt Elliott, Natalia Shpiro, C. James Hastie, Hilary Mclauchlan, Iva Klevernic, J. Simon C. Arthur, Dario R. Alessi, Philip Cohen

    Research output: Contribution to journalArticlepeer-review

    1979 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)297-315
    Number of pages19
    JournalBiochemical Journal
    Volume408
    DOIs
    Publication statusPublished - 15 Dec 2007

    Keywords

    • anti-cancer drugs
    • drug discovery
    • inhibitor specificity
    • kinase profiling
    • protein kinase
    • RECEPTOR TYROSINE KINASES
    • CYCLIN-DEPENDENT KINASES
    • RHO-ASSOCIATED KINASE
    • ISOFORMS IN-VITRO
    • P38 MAP KINASE
    • CELL-PROLIFERATION
    • TUMOR PROGRESSION
    • FAMILY-MEMBERS
    • SB 203580
    • P90 RSK

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