Pyrazolopyrimidines as dual Akt/p70S6K inhibitors

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• 作者：Kenneth D. Rice ; Moon H. Kim ; ^&dagger ; ; ^{mkim58@ncc.re.kr} ; Joerg Bussenius ; ^{jbusseni@exelixis.com} ; Neel K. Anand ; Charles M. Blazey ; Owen J. Bowles ; Lynne Canne-Bannen ; Diva S.-M. Chan ; Baili Chen ; Erick W. Co ; Simona Costanzo ; Steven C. DeFina ; Larisa Dubenko ; Stefan Engst ; Maurizio Franzini ; Ping Huang ; Vasu Jammalamadaka ; Richard G. Khoury ; Rhett R. Klein ; A.Douglas Laird ; Donna T. Le ; Morrison B. Mac ; David J. Matthews ; David Markby ; Nicole Miller ; John M. Nuss ; Jason J. Parks ; Tsze H. Tsang ; Amy L. Tsuhako ; Yong Wang ; Wei Xu
• 关键词：p70S6K inhibitor ; Akt inhibitor ; Pyrazolopyrimidine ; PI3K pathway ; Cancer
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 April, 2012
• 卷：22
• 期：8
• 页码：2693-2697
• 文件大小：522 K

摘要

Activation of the PI3K/Akt/mTOR kinase pathway is frequently associated with human cancer. Selective inhibition of p70S6Kinase, which is the last kinase in the PI3K pathway, is not sufficient for strong tumor growth inhibition and can lead to activation of upstream proteins including Akt through relief of a negative feedback loop. Targeting multiple sites in the PI3K pathway might be beneficial for optimal activity. In this manuscript we report the design of dual Akt/p70S6K inhibitors and the evaluation of the lead compound g class="boldFont">11bg> in vivo, which was eventually advanced into clinical development.