Imidazole piperazines: SAR and development of a potent class of cyclin-dependent kinase inhibitors with a novel binding mode
详细信息 查看全文
- 作者：M. Raymond V. Finlay ; David G. Acton ; David M. Andrews ; Andrew J. Barker ; Michael Dennis ; Eric Fisher ; Mark A. Graham ; Clive P. Green ; David W. Heaton ; Galith Karoutchi ; Sarah A. Loddick ; Ré ; my Mo
- 关键词：CDK ; Kinase ; Inhibitor ; Cancer
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2008
- 出版时间：1 August 2008
- 年：2008
- 卷：18
- 期：15
- 页码：4442-4446
- 全文大小：267 K
文摘
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.