Oxindole-based inhibitors of cyclin-dependent kinase 2 (CDK2): Design, synthesis, enzymatic activities, and X-ray crystallographic analysis
Oxindole-based inhibitors of cyclin-dependent kinase 2 (CDK2): Design, synthesis, enzymatic activities, and X-ray crystallographic analysis
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DOI：
10.1021/jm010117d
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发表时间：
2001-12-06
影响因子：
7.3
通讯作者：
Kuyper, LF
中科院分区：
文献类型：
--
作者：
Bramson, HN;Corona, J;Kuyper, LF
两个密切相关的氧吲哚类化合物，1h -吲哚-2,3-二酮3-苯基腙和3-（苯胺乙烯）-1,3-二氢- 2h -吲哚-2-酮，被证明能有效抑制细胞周期蛋白依赖性激酶2 （CDK2）。最初的先导化合物是作为3-苄基-1,3-二氢- 2h -吲哚-2- 1类激酶抑制剂的同源物制备的。结合CDK2的先导化合物的晶体学分析为类似物设计提供了依据。采用半自动化的配体对接方法选择化合物进行合成，并鉴定出许多对CDK2具有低纳摩尔抑制活性的化合物。用x射线晶体学对几种类似物的酶结合决定因子进行了评价。该系列化合物抑制CDK2的效力比抑制CDK1的效力高10倍。这类抑制剂的成员引起细胞周期的阻滞，并在预防化疗引起的脱发方面显示出潜在的效用。
Two closely related classes of oxindole-based compounds, 1H-indole-2,3-dione 3-phenylhydrazones and 3-(anilinomethylene)-1,3-dihydro-2H-indol-2-ones, were shown to potently inhibit cyclin-dependent kinase 2 (CDK2). The initial lead compound was prepared as a homologue of the 3-benzylidene-1,3-dihydro-2H-indol-2-one class of kinase inhibitor. Crystallographic analysis of the lead compound bound to CDK2 provided the basis for analogue design. A semiautomated method of ligand docking was used to select compounds for synthesis, and a number of compounds with low nanomolar inhibitory activity versus CDK2 were identified. Enzyme binding determinants for several analogues were evaluated by X-ray crystallography. Compounds in this series inhibited CDK2 with a potency similar to 10-fold greater than that for CDK1. Members of this class of inhibitor cause an arrest of the cell cycle and have shown potential utility in the prevention of chemotherapy-induced alopecia.