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咪唑哌嗪类：具有新型结合模式的一类强效细胞周期蛋白依赖性激酶抑制剂的构效关系及研发

Imidazole piperazines: SAR and development of a potent class of cyclin-dependent kinase inhibitors with a novel binding mode.

作者信息

Finlay M Raymond V, Acton David G, Andrews David M, Barker Andrew J, Dennis Michael, Fisher Eric, Graham Mark A, Green Clive P, Heaton David W, Karoutchi Galith, Loddick Sarah A, Morgentin Rémy, Roberts Andrew, Tucker Julie A, Weir Hazel M

机构信息

Cancer and Infection Research Area, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.

出版信息

Bioorg Med Chem Lett. 2008 Aug 1;18(15):4442-6. doi: 10.1016/j.bmcl.2008.06.027. Epub 2008 Jun 12.

DOI:10.1016/j.bmcl.2008.06.027
PMID:18617397
Abstract

A piperazine series of cyclin-dependent kinase (CDK) inhibitors have been identified. The compounds exhibit excellent physiochemical properties and a novel binding mode, whereby a bridging interaction via a water molecule with Asp 86 of CDK2, leads to selectivity for the CDK family of enzymes over other kinases. Piperazines 2e and 2i were subsequently shown to inhibit tumour growth when dosed orally in a nude mouse xenograft study. Additional chemical series that exploit this unexpected interaction with Asp 86 are also described.

摘要

已鉴定出一系列哌嗪类细胞周期蛋白依赖性激酶（CDK）抑制剂。这些化合物具有优异的物理化学性质和新颖的结合模式，即通过水分子与CDK2的天冬氨酸86形成桥连相互作用，从而使该酶对CDK家族具有相对于其他激酶的选择性。随后在裸鼠异种移植研究中口服给药时，哌嗪2e和2i显示出抑制肿瘤生长的作用。还描述了利用与天冬氨酸86这种意外相互作用的其他化学系列。

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