Discovery and Characterization of 2-Anilino-4-(Thiazol-5-yl)Pyrimidine Transcriptional CDK Inhibitors as Anticancer Agents
Discovery and Characterization of 2-Anilino-4-(Thiazol-5-yl)Pyrimidine Transcriptional CDK Inhibitors as Anticancer Agents
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DOI：
10.1016/j.chembiol.2010.07.016
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发表时间：
2010-10-29
影响因子：
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通讯作者：
Fischer, Peter M.
中科院分区：
文献类型：
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作者：
Wang, Shudong;Griffiths, Gary;Fischer, Peter M.
开发ATP拮抗剂激酶抑制剂的主要困难是靶点特异性，因为ATP结合基序存在于许多蛋白质中。我们介绍了一种策略，该策略使我们能够从激酶抑制剂文库中鉴定出阻断负责调节转录的细胞周期蛋白依赖性激酶的化合物，即，筛选级联采用基于有丝分裂指数和核p53蛋白积累的细胞表型测定。这使我们能够将化合物分类为转录、细胞周期，和有丝分裂抑制剂组我们描述了转录抑制剂类在激酶抑制谱、细胞作用模式和对转化细胞的选择性方面的特征。结构选择性原理用于优化效力和生物制药性质并导致转录抑制剂的开发，3，4-二甲基-5-[2-（4-哌嗪-1-基-苯基氨基）-嘧啶-4-基]-3H-噻唑-2-酮，在动物模型中具有抗癌活性
The main difficulty in the development of ATP antagonist kinase inhibitors is target specificity, since the ATP-binding motif is present in many proteins We introduce a strategy that has allowed us to identify compounds from a kinase inhibitor library that block the cyclin-dependent kinases responsible for regulating transcription, i e, CDK7 and especially CDK9 The screening cascade employs cellular phenotypic assays based on mitotic index and nuclear p53 protein accumulation This permitted us to classify compounds into transcriptional, cell cycle, and mitotic inhibitor groups We describe the charaterization of the transcriptional inhibitor class in terms of kinase inhibition profile, cellular mode of action, and selectivity for transformed cells A structural selectivity rationale was used to optimize potency and biopharmaceutical properties and led to the development of a transcriptional inhibitor, 3,4-dimethyl-5[2-(4-piperazin-1-yl-phenylamino)-pyrimidin-4-yl]-3H-thiazol-2-one, with anticancer activity in animal models