Structure-Guided Design of Potent and Selective Pyrimidylpyrrole Inhibitors of Extracellular Signal-Regulated Kinase (ERK) Using Conformational Control
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- 作者：Alex M. Aronov ; Qing Tang ; Gabriel Martinez-Botella ; Guy W. Bemis ; Jingrong Cao ; Guanjing Chen ; Nigel P. Ewing ; Pamella J. Ford ; Ursula A. Germann ; Jeremy Green ; Michael R. Hale ; Marc Jacobs ; James W.
- 刊名：Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：October 22, 2009
- 年：2009
- 卷：52
- 期：20
- 页码：6362-6368
- 全文大小：815K
- 年卷期：v.52,no.20(October 22, 2009)
- ISSN：1520-4804
文摘
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.