Imidazole piperazines: SAR and development of a potent class of cyclin-dependent kinase inhibitors with a novel binding mode
Imidazole piperazines: SAR and development of a potent class of cyclin-dependent kinase inhibitors with a novel binding mode
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DOI：
10.1016/j.bmcl.2008.06.027
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发表时间：
2008-08-01
影响因子：
2.7
通讯作者：
Weir, Hazel M.
中科院分区：
文献类型：
--
作者：
Finlay, M. Raymond V.;Acton, David G.;Weir, Hazel M.
哌嗪系列细胞周期蛋白依赖性激酶 (CDK) 抑制剂已被鉴定。这些化合物表现出优异的理化性质和新颖的结合模式，通过水分子与 CDK2 的 Asp 86 桥接相互作用，导致 CDK 家族酶相对于其他激酶具有选择性。随后在裸鼠异种移植研究中口服给药时哌嗪 2e 和 2i 被证明可以抑制肿瘤生长。还描述了利用与 Asp 86 的这种意想不到的相互作用的其他化学系列。 (c) 2008 Elsevier Ltd. 保留所有权利。
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. (c) 2008 Elsevier Ltd. All rights reserved.