Bain J, Plater L, Elliott M, Shapiro N, Hastie C, McLauchlan H, Klevernic I, Arthur J, Alessi D, Cohen PThe selectivity of protein kinase inhibitors: a further update. Biochem J 408:297-315

Division of Signal Transduction Therapy, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Biochemical Journal (Impact Factor: 4.4). 01/2008; 408(3):297-315. DOI: 10.1042/BJ20070797
Source: PubMed


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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    • "Recently, it has been shown that small molecule GSK3 inhibitors, including SB216763, inhibit, to a slightly lesser extent, other protein kinases in addition to GSK3β (Bain et al., 2007). For example, SB216763 inhibits DYRK1A, a serine/threonine kinase that plays a key role in hippocampal neurogenesis (Pons-Espinal et al., 2013). "
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    • "This is highly reminiscent of Aurora kinase B (AURKB) inhibitors, which have been shown to induce irregular-shaped nuclear formation with polyploidization (Ditchfield et al., 2003; Hauf et al., 2003). Indeed, the IRGs included some compounds (Aurora kinase inhibitor II and SU6656) that can inhibit AURK (Bain et al., 2007). "
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    • "Activation of AMPK leads to up-regulation of the anti-oxidative enzyme, heme oxygen- ase-1 (Li et al. 2012, 2013), which in hypertension may counteract the increased production of reactive oxygen species that contributes to the impairment of EDH-mediated relaxation (Li et al. 2013; Rashid et al. 2014). A caveat is that compound C, at the concentration used in the present experiments, only preferentially inhibits AMPK, but also competes for the ATP binding sites of other enzymes (Bain et al. 2007). Therefore, the interpretation based on the use of this pharmacological inhibitor warrants further investigation. "
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