Design and evaluation of a series of pyrazolopyrimidines as p70S6K inhibitors
- 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
- 期刊代码：10_0960894x
- 类别：ch
- 出版时间：15 March, 2012
- 卷：22
- 期：6
- 页码：2283-2286
- 文件大小：782 K
摘要
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 lass="boldFont">3a as active inhibitor. Lead optimization of lass="boldFont">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 lass="boldFont">13c.