Structure-guided design of purine-based probes for selective Nek2 inhibition.
Structure-guided design of purine-based probes for selective Nek2 inhibition.
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DOI：
10.18632/oncotarget.13249
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发表时间：
2017-03-21
期刊：
影响因子：
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通讯作者：
Cano C
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作者：
Coxon CR;Wong C;Bayliss R;Boxall K;Carr KH;Fry AM;Hardcastle IR;Matheson CJ;Newell DR;Sivaprakasam M;Thomas H;Turner D;Yeoh S;Wang LZ;Griffin RJ;Golding BT;Cano C
Nek 2（NIMA相关激酶2）是一种细胞周期依赖性丝氨酸/苏氨酸蛋白激酶，在有丝分裂开始时调节中心体分离。Nek 2的过表达在人类癌症中是常见的，并且抑制可以限制肿瘤细胞生长并促进凋亡。因此，用小分子抑制Nek 2为癌症的新疗法提供了前景。为了实现这一目标，需要更好地理解选择性抑制Nek 2的要求。6-烷氧基嘌呤类被鉴定为Nek 2和CDK 2的ATP竞争性抑制剂。与CDK 2抑制剂结构的比较表明，明智的6-烷氧基和2-芳氨基取代基的修饰可以实现Nek 2和CDK 2之间的歧视。本研究合成了2-芳氨基环上带有甲酰胺、磺酰胺和脲取代基的6-环己基甲氧基-2-芳氨基嘌呤化合物库。这些化合物中很少有对Nek 2的选择性超过CDK 2，最好的结果是3-（（6-（环己基甲氧基）-9H-嘌呤-2-基）氨基）-N，N-二甲基苯甲酰胺（CDK 2 IC 50 = 7.0 μM; Nek 2 IC 50 = 0.62 μM），选择性>10倍。6-取代基的缺失消除了针对Nek 2和CDK 2的活性。在C-6位含有（E）-二烷基氨基乙烯基取代基的9种化合物均显示出对Nek 2的选择性，例如（E）-6-（2-（氮杂环庚烷-1-基）乙烯基）-N-苯基-9H-嘌呤-2-胺（CDK 2 IC 50 = 2.70 μM; Nek 2 IC 50 = 0.27 μM）。所选化合物的结构生物学使所观察到的Nek 2激活的结构活性关系和机制部分合理化。这表明羧酰胺11是第一个报道的DFG-in构象的Nek 2抑制剂。
Nek2 (NIMA-related kinase 2) is a cell cycle-dependent serine/threonine protein kinase that regulates centrosome separation at the onset of mitosis. Overexpression of Nek2 is common in human cancers and suppression can restrict tumor cell growth and promote apoptosis. Nek2 inhibition with small molecules, therefore, offers the prospect of a new therapy for cancer. To achieve this goal, a better understanding of the requirements for selective-inhibition of Nek2 is required. 6-Alkoxypurines were identified as ATP-competitive inhibitors of Nek2 and CDK2. Comparison with CDK2-inhibitor structures indicated that judicious modification of the 6-alkoxy and 2-arylamino substituents could achieve discrimination between Nek2 and CDK2. In this study, a library of 6-cyclohexylmethoxy-2-arylaminopurines bearing carboxamide, sulfonamide and urea substituents on the 2-arylamino ring was synthesized. Few of these compounds were selective for Nek2 over CDK2, with the best result being obtained for 3-((6-(cyclohexylmethoxy)-9H-purin-2-yl)amino)-N,N-dimethylbenzamide (CDK2 IC50 = 7.0 μM; Nek2 IC50 = 0.62 μM) with >10-fold selectivity. Deletion of the 6-substituent abrogated activity against both Nek2 and CDK2. Nine compounds containing an (E)-dialkylaminovinyl substituent at C-6, all showed selectivity for Nek2, e.g. (E)-6-(2-(azepan-1-yl)vinyl)-N-phenyl-9H-purin-2-amine (CDK2 IC50 = 2.70 μM; Nek2 IC50 = 0.27 μM). Structural biology of selected compounds enabled a partial rationalization of the observed structure activity relationships and mechanism of Nek2 activation. This showed that carboxamide 11 is the first reported inhibitor of Nek2 in the DFG-in conformation.