Structure-Guided Design of Potent and Selective Pyrimidylpyrrole Inhibitors of Extracellular Signal-Regulated Kinase (ERK) Using Conformational Control

被引：136

作者：

Aronov, Alex M. ^{[1
]}

Tang, Qing ^{[1
]}

Martinez-Botella, Gabriel ^{[1
]}

Bemis, Guy W. ^{[1
]}

Cao, Jingrong ^{[1
]}

Chen, Guanjing ^{[1
]}

Ewing, Nigel P. ^{[1
]}

Ford, Pamella J. ^{[1
]}

Germann, Ursula A. ^{[1
]}

Green, Jeremy ^{[1
]}

Hale, Michael R. ^{[1
]}

Jacobs, Marc ^{[1
]}

Janetka, James W. ^{[1
]}

Maltais, Francois ^{[1
]}

Markland, William ^{[1
]}

Namchuk, Mark N. ^{[1
]}

Nanthakumar, Suganthini ^{[1
]}

Poondru, Srinivasu ^{[1
]}

Straub, Judy ^{[1
]}

ter Haar, Ernst ^{[1
]}

Xie, Xiaoling ^{[1
]}

机构：

[1] Vertex Pharmaceut Inc, Cambridge, MA 02139 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 20期

关键词：

ACCURATE DOCKING; PATHWAY; CANCER; GLIDE;

D O I：

10.1021/jm900630q

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 Ras/Raf/MEK/ERK signal transduction, an oncogenic pathway implicated in a variety of human cancers, is a key target in anticancer drug design. A novel series of pyrimidylpyrrole ERK inhibitors has been identified. Discovery of a conformational change for lead compound 2, when bound to ERK2 relative to antitarget GSK3, enabled structure-guided selectivity optimization, which led to the discovery of 11e, a potent, selective, and orally bioavailable inhibitor of ERK.

引用

页码：6362 / 6368

页数：7

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