A quantitative analysis of kinase inhibitor selectivity
A quantitative analysis of kinase inhibitor selectivity
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DOI：
10.1038/nbt1358
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发表时间：
2008-01-01
影响因子：
46.9
通讯作者：
Zarrinkar, Patrick P.
中科院分区：
文献类型：
--
作者：
Karaman, Mazen W.;Herrgard, Sanna;Zarrinkar, Patrick P.
激酶抑制剂是一类新的治疗药物，具有抑制多个靶点的倾向（1，2）。多激酶活性的生物学后果定义不清，了解选择性、有效性和安全性之间关系的重要一步是探索抑制剂如何与人激酶组相互作用（2-4）。我们在一组317种激酶中呈现了38种激酶抑制剂的相互作用图，这些激酶代表了预测的人类蛋白激酶组的50%以上。这些数据构成了迄今为止对激酶抑制剂选择性的最全面的研究，并揭示了多种多样的相互作用模式。为了能够对结果进行全局分析，我们引入了选择性得分的概念，作为量化和区分所观察到的相互作用模式的通用工具。我们进一步研究了检测板大小的影响，发现小型检测板无法提供可靠的选择性测量。
Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets(1,2). The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome(2-4). We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.