Comprehensive analysis of kinase inhibitor selectivity
Comprehensive analysis of kinase inhibitor selectivity
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DOI：
10.1038/nbt.1990
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发表时间：
2011-11-01
影响因子：
46.9
通讯作者：
Zarrinkar, Patrick P.
中科院分区：
文献类型：
--
作者：
Davis, Mindy I.;Hunt, Jeremy P.;Zarrinkar, Patrick P.
我们测试了72种激酶抑制剂与442种激酶的相互作用，这些激酶覆盖了80%的人类催化蛋白激酶组。我们的数据显示，作为一类，II型抑制剂比I型抑制剂更具选择性，但这一趋势也有重要的例外。数据进一步说明，选择性抑制剂已开发针对大多数激酶的化合物测试。相互作用模式的分析揭示了一类“群选择性”抑制剂对单个激酶亚家族广泛有效，但在该亚家族之外具有选择性。该数据集建议使用化合物作为工具来研究没有专用抑制剂存在的激酶。这也为进一步探索激酶抑制剂的生物学和毒性以及研究所观察到的相互作用模式的结构基础奠定了基础。我们的发现将有助于实现基因组学在药物开发和细胞信号基础研究方面的直接潜力。
We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.