Design and evaluation of a series of pyrazolopyrimidines as p70S6K inhibitors
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- 作者：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 ; Moon H. Kim ; Rhett R. Klein ; 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 ; Kenneth D. Rice
- 关键词：p70S6K inhibitor ; Pyrazolopyrimidine ; PI3K pathway ; Cancer
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：15 March, 2012
- 年：2012
- 卷：22
- 期：6
- 页码：2283-2286
- 全文大小：782 K
文摘
The 70-kDa ribosomal protein S6 kinase (p70S6K) is part of the PI3K/AKT/mTOR pathway and has been implicated in cancer. High throughput screening versus p70S6K led to the identification of aminopyrimidine 3a as active inhibitor. Lead optimization of 3a resulted in highly potent, selective, and orally bioavailable pyrazolopyrimidines. In this manuscript we report the structure-activity relationship of this series and pharmacokinetic, pharmacodynamic, and efficacy data of the lead compound 13c.