Aminopyridine-Based c-Jun N-Terminal Kinase Inhibitors with Cellular Activity and Minimal Cross-Kinase Activity
| Autor: | James M. Trevillyan, Elizabeth H. Fry, Eric F. Johnson, Chaohong Sun, Hing L. Sham, Charles W. Hutchins, Thomas H. Lubben, Bruce G. Szczepankiewicz, Edward T. Olejniczak, Michael A. Stashko, Cele Abad-Zapatero, Michael D. Serby, Rebecca J. Gum, Hongyu Zhao, Kristi Haskins, Zhili Xin, Bo Liu, Sarah A Dorwin, Jill E. Clampit, Nelson Lissa T, Gang Liu, Mei Liu, Christi Kosogof, Cristina M. Rondinone, Sanyi Wang, Deanna L. Haasch |
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| Rok vydání: | 2006 |
| Předmět: |
Models
Molecular Protein Conformation Aminopyridines Biological Availability Crystallography X-Ray MAP2K7 Rats Sprague-Dawley Mitogen-Activated Protein Kinase 10 Cell Line Tumor Drug Discovery Animals Humans Mitogen-Activated Protein Kinase 9 Mitogen-Activated Protein Kinase 8 ASK1 Phosphorylation Kinase activity Protein kinase A MAPK14 biology Kinase Chemistry c-jun Rats Biochemistry Mitogen-activated protein kinase biology.protein Molecular Medicine Half-Life |
| Zdroj: | Journal of Medicinal Chemistry. 49:3563-3580 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm060199b |
| Popis: | The c-Jun N-terminal kinases (JNK-1, -2, and -3) are members of the mitogen activated protein (MAP) kinase family of enzymes. They are activated in response to certain cytokines, as well as by cellular stresses including chemotoxins, peroxides, and irradiation. They have been implicated in the pathology of a variety of different diseases with an inflammatory component including asthma, stroke, Alzheimer's disease, and type 2 diabetes mellitus. In this work, high-throughput screening identified a JNK inhibitor with an excellent kinase selectivity profile. Using X-ray crystallography and biochemical screening to guide our lead optimization, we prepared compounds with inhibitory potencies in the low-double-digit nanomolar range, activity in whole cells, and pharmacokinetics suitable for in vivo use. The new compounds were over 1,000-fold selective for JNK-1 and -2 over other MAP kinases including ERK2, p38alpha, and p38delta and showed little inhibitory activity against a panel of 74 kinases. |
| Databáze: | OpenAIRE |
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