Discovery of Novel Allosteric Mitogen-Activated Protein Kinase Kinase (MEK) 1,2 Inhibitors Possessing Bidentate Ser212 Interactions
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- 作者：Robert A. Heald ; Philip Jackson ; Pascal Savy ; Mark Jones ; Emanuela Gancia ; Brenda Burton ; Richard Newman ; Jason Boggs ; Emily Chan ; Jocelyn Chan ; Edna Choo ; Mark Merchant ; Patrick Rudewicz ; Mark Ultsch ; Christian Wiesmann ; Qin Yue ; Marcia Belvin ; Steve Price
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：May 24, 2012
- 年：2012
- 卷：55
- 期：10
- 页码：4594-4604
- 全文大小：454K
- 年卷期：v.55,no.10(May 24, 2012)
- ISSN：1520-4804
文摘
Using structure-based design, two novel series of highly potent biaryl amine mitogen-activated protein kinase kinase (MEK) inhibitors have been discovered. These series contain an H-bond acceptor, in a shifted position compared with previously disclosed compounds, and an adjacent H-bond donor, resulting in a bidentate interaction with the Ser212 residue of MEK1. The most potent compound identified, 1 (G-894), is orally active in in vivo pharmacodynamic and tumor xenograft models.