Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, Old Road Campus, University of Oxford, Oxford, UK.
Nanosyn, Inc., Santa Clara, California, USA.
Nat Biotechnol. 2016 Jan;34(1):95-103. doi: 10.1038/nbt.3374. Epub 2015 Oct 26.
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.
尽管蛋白激酶抑制剂作为已批准的治疗药物取得了成功，但药物发现仍集中在一小部分激酶靶点上。在这里，我们全面描述了已发表的激酶抑制剂集（PKIS），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，并作为开源靶标验证的实验。我们使用 224 种重组激酶和 24 种 G 蛋白偶联受体在活性测定中筛选该抑制剂集，并在癌细胞增殖和血管生成的细胞测定中筛选。我们确定了设计新的孤儿激酶化学探针的化学起点，并通过开发先前未靶向的激酶 LOK 和 SLK 的选择性抑制剂说明了这些先导化合物的实用性。我们的细胞筛选揭示了可调节体外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一种提高对历史上未靶向激酶组理解的有效方法。
