Design and evaluation of a series of pyrazolopyrimidines as p70S6K inhibitors

被引：25

作者：

Bussenius, Joerg ^{[1
]}

Anand, Neel K. ^{[1
]}

Blazey, Charles M. ^{[1
]}

Bowles, Owen J. ^{[1
]}

Bannen, Lynne Canne ^{[1
]}

Chan, Diva S. -M. ^{[1
]}

Chen, Baili ^{[1
]}

Co, Erick W. ^{[1
]}

Costanzo, Simona ^{[1
]}

DeFina, Steven C. ^{[1
]}

Dubenko, Larisa ^{[1
]}

Engst, Stefan ^{[1
]}

Franzini, Maurizio ^{[1
]}

Huang, Ping ^{[1
]}

Jammalamadaka, Vasu ^{[1
]}

Khoury, Richard G. ^{[1
]}

Kim, Moon H. ^{[1
]}

Klein, Rhett R. ^{[1
]}

Laird, Douglas ^{[1
]}

Le, Donna T. ^{[1
]}

Mac, Morrison B. ^{[1
]}

Matthews, David J. ^{[1
]}

Markby, David ^{[1
]}

Miller, Nicole ^{[1
]}

Nuss, John M. ^{[1
]}

Parks, Jason J. ^{[1
]}

Tsang, Tsze H. ^{[1
]}

Tsuhako, Amy L. ^{[1
]}

Wang, Yong ^{[1
]}

Xu, Wei ^{[1
]}

Rice, Kenneth D. ^{[1
]}

机构：

[1] Exelixis, San Francisco, CA 94080 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 06期

关键词：

p70S6K inhibitor; Pyrazolopyrimidine; PI3K pathway; Cancer; HUMAN CANCER; PATHWAY;

D O I：

10.1016/j.bmcl.2012.01.105

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

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 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. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：2283 / 2286

页数：4

共 11 条

[1]

4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: Potent and selective p70S6 kinase inhibitors [J].