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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Promiscuity analysis of a kinase panel screen with designated p38 alpha inhibitors
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Promiscuity analysis of a kinase panel screen with designated p38 alpha inhibitors

机译：具有指定P38α抑制剂激酶面板筛网的滥交分析

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摘要

Protein phosphorylation by kinases is of critical importance for the regulation of many cellular functions. When kinases are deregulated numerous biological processes are affected, which may cause a variety of diseases. Therefore, kinase inhibition plays an important role for therapeutic intervention. A number of kinase inhibitors have been approved as drugs, initially in oncology where promiscuous (multi-kinase) inhibitors were most efficacious. Exploring kinase inhibitor selectivity and promiscuity for therapy is among the most challenging aspects of kinase drug discovery. Herein, we thoroughly analyze a kinase profiling experiment in which 637 designated inhibitors of p38 alpha MAP kinase (p38 alpha) were tested against a panel of 60 kinases distributed across the human kinome. In this experiment, only 19% of the inhibitors were found to be promiscuous when the median p38 alpha inhibition level was applied as an activity threshold. Promiscuous inhibitors had a median value of two targets per compound, and many of these inhibitors were only active against the p38 alpha and closely related JNK3 enzymes. Promiscuity cliffs were identified and analyzed in a network representation revealing structural modifications that were implicated in triggering compound promiscuity. Taken together, the findings revealed a high degree of selectivity of designated p38 alpha directed inhibitors although they target the ATP binding site that is largely conserved across the human kinome. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：激酶蛋白质磷酸化对许多细胞功能的调节至关重要。当激酶解毒时，许多生物过程受到影响，这可能导致各种疾病。因此，激酶抑制起到治疗干预的重要作用。许多激酶抑制剂已被批准为药物，最初在肿瘤学中，诱导（多激酶）抑制剂最有效。探索激酶抑制剂选择性和治疗滥用是激酶药物发现中最具挑战性的方面。在此，我们彻底分析了激酶分析实验，其中测试了P38α映射激酶（P38α）的637个指定抑制剂，用于分布在人牛体上的60个激酶面板。在该实验中，当施用中值P38α抑制水平作为活性阈值时，仅发现19％的抑制剂是混杂的。混杂抑制剂具有每种化合物的两个靶标的中值值，并且许多这些抑制剂仅针对P38α和密切相关的JNK3酶活性。在网络表示中识别并分析滥交悬崖，揭示涉及触发复合滥用的结构修改。在一起，发现表明指定的P38α靶向抑制剂的高度选择性，尽管它们靶向在人为Kinome上大部分保存的ATP结合位点。 （c）2019年Elsevier Masson SAS。版权所有。

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