Discovery and SAR of oxindole-pyridine-based protein kinase B/Akt inhibitors for treating cancers

被引：51
|
作者：
Zhu, GD [1 ]
Gandhi, VB
Gong, JC
Luo, Y
Liu, XS
Shi, Y
Guan, R
Magnone, SR
Klinghofer, V
Johnson, EF
Bouska, J
Shoemaker, A
Oleksijew, A
Jarvis, K
Park, C
De Jong, R
Oltersdorf, T
Li, Q
Rosenberg, SH
Giranda, VL
机构：
[1] Abbott Labs, GPRD, Canc Res, Abbott Pk, IL 60064 USA
[2] Abbott Labs, GPRD, Struct Biol, Abbott Pk, IL 60064 USA
[3] IDUN Pharmaceut Inc, San Diego, CA 92121 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 13期
关键词：
Akt inhibitor; protein kinase B; PKB; GSK3; FL5.12-Akt; anticancer;
D O I：
10.1016/j.bmcl.2006.04.005
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
We describe a series of potent and selective oxindole-pyridine-based protein kinase B/Akt inhibitors. The most potent compound 11n in this series demonstrated an IC50 of 0.17 nM against Akt1 and more than 100-fold selectivity over other Akt isozymes. The selectivity against other protein kinases was highly dependent on the C-3 substitutions at the oxindole scaffold, with unsubstituted 9e or 3-furan-2-ylmethylene (11n) more selective and 3-(1H-pyrrol-2-yl)methylene (11f) or 3-(1H-imidazol-2-yl)methylene (Ilk) less selective. In a mouse xenograft model, 9d, 11f, and 11n inhibited tumor growth but with accompanying toxicity. (c) 2006 Elsevier Ltd. All rights reserved.
引用
收藏
页码：3424 / 3429
页数：6
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