极光激酶的一种高选择性抑制剂的特性分析
Characterization of a highly selective inhibitor of the Aurora kinases.
作者信息
Ferguson Fleur M, Doctor Zainab M, Chaikuad Apirat, Sim Taebo, Kim Nam Doo, Knapp Stefan, Gray Nathanael S
机构信息
Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom; Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Goethe University, Max-von Laue Str. 9, 60438 Frankfurt am Main, Germany.
出版信息
Bioorg Med Chem Lett. 2017 Sep 15;27(18):4405-4408. doi: 10.1016/j.bmcl.2017.08.016. Epub 2017 Aug 10.
Aurora kinases play an essential role in mitosis and cell cycle regulation. In recent years Aurora kinases have proved popular cancer targets and many inhibitors have been developed. The majority of these clinical candidates are multi-targeted, rendering them inappropriate as tools for studying Aurora kinase mediated signaling. Here we report discovery of a highly selective inhibitor of Aurora kinases A, B and C, with potent cellular activity and minimal off-target activity (PLK4). The X-ray co-crystal structure of Aurora A in complex with compound 2 is reported, and provides insights into the structural determinants of ligand binding and selectivity.
极光激酶在有丝分裂和细胞周期调控中发挥着至关重要的作用。近年来，极光激酶已被证明是热门的癌症靶点，并且已经开发出许多抑制剂。这些临床候选药物大多具有多靶点作用，使其不适用于作为研究极光激酶介导信号传导的工具。在此，我们报告发现了一种对极光激酶A、B和C具有高度选择性的抑制剂，具有强大的细胞活性和最小的脱靶活性（PLK4）。报道了极光激酶A与化合物2复合物的X射线共晶体结构，并提供了关于配体结合和选择性的结构决定因素的见解。
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