Azole-based inhibitors of AKT/PKB for the treatment of cancer

被引：15

作者：

Zeng, Qingping ^{[1
]}

Allen, John G. ^{[1
]}

Bourbeau, Matthew P. ^{[1
]}

Wang, Xianghong ^{[1
]}

Yao, Guomin ^{[1
]}

Tadesse, Seifu ^{[1
]}

Rider, James T. ^{[1
]}

Yuan, Chester C. ^{[1
]}

Hong, Fang-Tsao ^{[1
]}

Lee, Matthew R. ^{[1
]}

Zhang, Shiwen ^{[2
]}

Lofgren, Julie A. ^{[2
]}

Freeman, Daniel J. ^{[2
]}

Yang, Suijin ^{[2
]}

Li, Chun ^{[3
]}

Tominey, Elizabeth ^{[3
]}

Huang, Xin ^{[4
]}

Hoffman, Douglas ^{[5
]}

Yamane, Harvey K. ^{[6
]}

Fotsch, Christopher ^{[1
]}

Dominguez, Celia ^{[1
]}

Hungate, Randall ^{[1
]}

Zhang, Xiaoling ^{[2
]}

机构：

[1] Amgen Inc, Chem Res & Discovery, Thousand Oaks, CA 91320 USA

[2] Amgen Inc, Oncol Res, Thousand Oaks, CA 91320 USA

[3] Amgen Inc, Pharmacokinet & Drug Metab, Thousand Oaks, CA 91320 USA

[4] Amgen Inc, Chem Res & Discovery, Cambridge, MA 02142 USA

[5] Amgen Inc, Small Mol Proc & Product Dev, Thousand Oaks, CA 91320 USA

[6] Amgen Inc, Prot Sci, Thousand Oaks, CA 91320 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 05期

关键词：

PKB; AKT; Cancer; SAR studies; PI3K/AKT PATHWAY; AKT; TUMORIGENESIS; OPTIMIZATION;

D O I：

10.1016/j.bmcl.2010.01.067

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Through a combination of screening and structure-based rational design, we have discovered a series of N-1-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：1559 / 1564

页数：6

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