Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity.
Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity.
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DOI：
10.1038/nbt.2017
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发表时间：
2011-10-30
影响因子：
46.9
通讯作者：
中科院分区：
文献类型：
--
作者：
小分子蛋白激酶抑制剂是阐明细胞信号通路的重要工具，是有前途的治疗药物。由于ATP结合位点的进化保守性，靶向该位点的大多数激酶抑制剂混杂地抑制多种激酶。利用这些化合物的实验的解释是混淆的综合激酶选择性的大多数抑制剂的数据缺乏。在这里，我们分析了178个商业上可用的激酶抑制剂对300个重组蛋白激酶的面板使用功能测定的活性。定量分析揭示了复杂的，往往是意想不到的激酶抑制剂的相互作用，具有广泛的滥交。许多脱靶相互作用与看似无关的激酶发生，揭示了如何大规模分析可用于识别特定，不同激酶的多靶点抑制剂。这些结果对药物开发具有重要意义，并为选择化合物以阐明激酶功能和解释使用它们的实验结果提供了资源。
Small-molecule protein kinase inhibitors are central tools for elucidating cellular signaling pathways and are promising therapeutic agents. Due to evolutionary conservation of the ATP-binding site, most kinase inhibitors that target this site promiscuously inhibit multiple kinases. Interpretation of experiments utilizing these compounds is confounded by a lack of data on the comprehensive kinase selectivity of most inhibitors. Here we profiled the activity of 178 commercially available kinase inhibitors against a panel of 300 recombinant protein kinases using a functional assay. Quantitative analysis revealed complex and often unexpected kinase-inhibitor interactions, with a wide spectrum of promiscuity. Many off-target interactions occur with seemingly unrelated kinases, revealing how large-scale profiling can be used to identify multi-targeted inhibitors of specific, diverse kinases. The results have significant implications for drug development and provide a resource for selecting compounds to elucidate kinase function and for interpreting the results of experiments that use them.
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影响因子：
--
作者：
Miduturu CV;Deng X;Kwiatkowski N;Yang W;Brault L;Filippakopoulos P;Chung E;Yang Q;Schwaller J;Knapp S;King RW;Lee JD;Herrgard S;Zarrinkar P;Gray NS
通讯作者：
Gray NS
DOI：
10.1073/pnas.0708800104
发表时间：
2007-12-18
影响因子：
11.1
作者：
Fedorov, Oleg;Marsden, Brian;Knapp, Stefan
通讯作者：
Knapp, Stefan
影响因子：
7.3
作者：
Bamborough, Paul;Drewry, David;Schneider, Klaus
通讯作者：
Schneider, Klaus
影响因子：
8
作者：
Huertas, D.;Soler, M.;Moreto, J.;Villanueva, A.;Martinez, A.;Vidal, A.;Charlton, M.;Moffat, D.;Patel, S.;McDermott, J.;Owen, J.;Brotherton, D.;Krige, D.;Cuthill, S.;Esteller, M.
通讯作者：
Esteller, M.
影响因子：
46.9
作者：
Fabian, MA;Biggs, WH;Lockhart, DJ
通讯作者：
Lockhart, DJ