The selectivity of protein kinase inhibitors: a further update
The selectivity of protein kinase inhibitors: a further update
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DOI：
10.1042/bj20070797
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发表时间：
2007-12-15
影响因子：
4.1
通讯作者：
Cohen, Philip
中科院分区：
文献类型：
--
作者：
Bain, Jenny;Plater, Lorna;Cohen, Philip
65种被报道为蛋白激酶相对特异性抑制剂的化合物的特异性已经对一组70-80个蛋白激酶进行了分析。根据这些信息，以及我们在细胞中研究的化合物的作用和文献中的其他数据，我们建议使用以下小分子抑制剂：SB 203580/SB202190和BIRB 0796将平行用于评估p38 MAPK（丝裂原活化蛋白激酶）异构体的生理作用，PI-103和wortmannin将平行用于抑制磷脂酰肌醇（磷酸肌醇）3-激酶，PP1或PP2将平行用于Src- i1 （Src抑制剂-1）抑制Src家族成员；PD 184352或PD 0325901抑制MKK1 （MAPK激酶-1）或MKK1 + MKK5， Akt- i -1/2抑制PKB（蛋白激酶B/Akt）的激活，雷帕霉素抑制TORC1 [mTOR（哺乳动物雷帕霉素靶蛋白）-raptor （mTOR的调控相关蛋白）复合物]，CT 99021抑制GSK3（糖原合成酶激酶3），bid1870和SL0101或FMK（荧光甲基酮）平行用于抑制RSK（核糖体S6激酶），D4476抑制CK1（酪蛋白激酶1），VX680抑制极光激酶，罗斯科维汀作为泛cdk（细胞周期蛋白依赖性激酶）抑制剂。我们还在体外鉴定了鼠碱是DYRK1A（双特异性酪氨酸磷酸化和调节激酶1A）的有效和特异性抑制剂。这些结果进一步强调了在使用蛋白激酶的小分子抑制剂来评估这些酶的生理作用时需要相当谨慎。尽管被广泛使用，但我们分析的许多化合物过于非特异性，无法得出有用的结论，只能排除细胞过程中特定蛋白激酶的参与。
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.