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Structure-based design and synthesis of bicyclic fused-pyridines as MEK inhibitors
Institution:1. Center for Integrated Molecular Brain Imaging (CIMBI), Rigshospitalet and University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark;2. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark;1. Syncom B.V., Kadijk 3, Groningen 9747 AT, The Netherlands;2. Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands;1. Department of Biochemistry, University of Washington, Seattle, WA 98195, United States;2. Laboratorio de Enzimología de Parásitos, Facultad de Ciencias, Universidad de los Andes, Mérida, Venezuela;3. Department of Medicine, Division of Allergy and Infectious Diseases, and the Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, WA 98109, United States;1. Industrial Technology Center of Nagasaki, 2-1303-8, Ikeda, Omura, Nagasaki 856-0026, Japan;2. Graduate School of Engineering, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8131, Japan;3. Faculty of Pharmaceutical Sciences, Kobe Pharmaceutical University, 4-19-1 Motoyamakita Machi, Higashinada Ku, Kobe 658-8558, Japan;4. Faculty of Environmental Studies, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8131, Japan;5. Department of Chemistry, Tamkang University, Tamsui 251, Taiwan
Abstract:The MAPK pathway is identified as one of the most important pathways involved in cell proliferation and differentiation. A key kinase in the pathway, the Mitogen-activated protein kinase kinase (MEK) is recognized as a promising target for antitumor drugs. Structure-based design and optimization of known MEK inhibitors resulted in identification of compound 10a as a potent non-ATP competitive MEK inhibitor in both in vitro and in vivo tests.
Keywords:MEK  Bicyclic  Fused-pyridine  Cancer  SBDD
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