Wang Shudong, Griffiths Gary, Midgley Carol A, Barnett Anna L, Cooper Michael, Grabarek Joanna, Ingram Laura, Jackson Wayne, Kontopidis George, McClue Steven J, McInnes Campbell, McLachlan Janice, Meades Christopher, Mezna Mokdad, Stuart Iain, Thomas Mark P, Zheleva Daniella I, Lane David P, Jackson Robert C, Glover David M, Blake David G, Fischer Peter M
Cyclacel Limited, Dundee DD15JJ, Scotland, UK.
Chem Biol. 2010 Oct 29;17(10):1111-21. doi: 10.1016/j.chembiol.2010.07.016.
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 characterization 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.
ATP拮抗剂激酶抑制剂开发中的主要困难在于靶点特异性，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可阻断负责调节转录的细胞周期蛋白依赖性激酶（即CDK7，尤其是CDK9）的化合物。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分析。这使我们能够将化合物分为转录抑制剂、细胞周期抑制剂和有丝分裂抑制剂组。我们从激酶抑制谱、细胞作用模式和对转化细胞的选择性方面描述了转录抑制剂类别的特征。利用结构选择性原理优化了效力和生物制药特性，并导致开发出一种在动物模型中具有抗癌活性的转录抑制剂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。
