The selectivity of protein kinase inhibitors; a further update
Résumé
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. Based on 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 of the physiological roles of p38 MAPK isoforms, PI-103 and wortmannin to be used in parallel to inhibit PI 3-kinase, PP1 or PP2 to be used in parallel with Src inhibitor-1 to inhibit Src family members; PD 184352 or PD 0325901 to inhibit MKK1 or MKK1 plus MKK5, Akt-I-1/2 to inhibit the activation of PKB/AKT, rapamycin to inhibit TORC1, CT 99021 to inhibit GSK3, BI-D1870 and SL0101 or FMK to be used in parallel to inhibit RSK, D4476 to inhibit CK1, VX680 to inhibit Aurora kinases and roscovitine as a pan CDK inhibitor. We have also identified harmine as a very potent and specific inhibitor of DYRK1A in vitro. The results have further emphasised 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 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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