Comprehensive characterization of the Published Kinase Inhibitor Set
Comprehensive characterization of the Published Kinase Inhibitor Set
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DOI：
10.1038/nbt.3374
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发表时间：
2016-01-01
影响因子：
46.9
通讯作者：
Zuercher, William J.
中科院分区：
文献类型：
--
作者：
Elkins, Jonathan M.;Fedele, Vita;Zuercher, William J.
尽管蛋白激酶抑制剂作为批准的治疗方法取得了成功，但药物发现仍集中在一小部分激酶靶标上。在这里，我们提供了已发布的激酶抑制剂集 (PKIS) 的全面表征，这是一组 367 种小分子 ATP 竞争性激酶抑制剂，最近免费提供，旨在扩大该领域的研究并作为开源靶点验证的实验。我们通过 224 种重组激酶和 24 G 蛋白偶联受体的活性测定以及癌细胞增殖和血管生成的细胞测定来筛选该组。我们确定了设计新的孤儿激酶化学探针的化学起点，并通过为以前未靶向的激酶 LOK 和 SLK 开发选择性抑制剂来说明这些先导化合物的实用性。我们的细胞筛选揭示了在体外调节癌细胞生长和血管生成的化合物。这些试剂和相关数据说明了增进对历史上非靶向激酶组的了解的有效方法。
Despite the success of protein kinase inhibitors as approved therapeutics, drug discovery has focused on a small subset of kinase targets. Here we provide a thorough characterization of the Published Kinase Inhibitor Set (PKIS), a set of 367 small molecule ATP-competitive kinase inhibitors that was recently made freely available with the aim of expanding research in this field and as an experiment in open-source target validation. We screen the set in activity assays with 224 recombinant kinases and 24 G protein-coupled receptors and in cellular assays of cancer cell proliferation and angiogenesis. We identify chemical starting points for designing new chemical probes of orphan kinases and illustrate the utility of these leads by developing a selective inhibitor for the previously untargeted kinases LOK and SLK. Our cellular screens reveal compounds that modulate cancer cell growth and angiogenesis in vitro. These reagents and associated data illustrate an efficient way forward to increasing understanding of the historically untargeted kinome.