Discovery of novel allosteric mitogen-activated protein kinase kinase (MEK) 1, 2 inhibitors possessing bidentate Ser212 interactions

…, M Jones, E Gancia, B Burton, R Newman…

文献索引：Heald, Robert A.; Jackson, Philip; Savy, Pascal; Jones, Mark; Gancia, Emanuela; Burton, Brenda; Newman, Richard; Boggs, Jason; Chan, Emily; Chan, Jocelyn; Choo, Edna; Merchant, Mark; Rudewicz, Patrick; Ultsch, Mark; Wiesmann, Christian; Yue, Qin; Belvin, Marcia; Price, Steve Journal of Medicinal Chemistry, 2012 , vol. 55, # 10 p. 4594 - 4604

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被引用次数: 23

摘要

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 ...