Discovery of Novel Allosteric Mitogen-Activated Protein Kinase Kinase (MEK) 1,2 Inhibitors Possessing Bidentate Ser212 Interactions
Journal of Medicinal Chemistry2012Vol. 55(10), pp. 4594–4604
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Robert A. Heald, Philip S. Jackson, Pascal Savy, Mark Jones, Emanuela Gancia, Brenda Burton, Richard Newman, Jason Boggs, Emily Chan, Jocelyn Chan, Edna F. Choo, Mark Merchant, Patrick J. Rudewicz, Mark Ultsch, Christian Wiesmann, Yue Qin, Marcia Belvin, Steve Price
Abstract
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.
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