Abstract
Pyrazole-based inhibitors of the transforming growth factor-beta type I receptor kinase domain (TbetaR-I) are described. Examination of the SAR in both enzyme- and cell-based in vitro assays resulted in the emergence of two subseries featuring differing selectivity versus p38 MAP kinase. A common binding mode at the active site has been established by successful cocrystallization and X-ray analysis of potent inhibitors with the TbetaR-I receptor kinase domain.
MeSH terms
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3T3 Cells
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Adenosine Triphosphate / metabolism
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Animals
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Benzene Derivatives / chemical synthesis*
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Benzene Derivatives / chemistry
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Benzene Derivatives / metabolism
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Benzene Derivatives / pharmacology*
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Binding Sites
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Cell Line
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Crystallography, X-Ray
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology*
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Humans
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Inhibitory Concentration 50
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Mice
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Mink
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Models, Molecular
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / chemistry
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Protein Structure, Tertiary
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / metabolism
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Pyrazoles / pharmacology*
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
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Receptors, Transforming Growth Factor beta / chemistry
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Receptors, Transforming Growth Factor beta / metabolism
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Spodoptera
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Structure-Activity Relationship
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p38 Mitogen-Activated Protein Kinases
Substances
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Benzene Derivatives
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Enzyme Inhibitors
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Pyrazoles
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Receptors, Transforming Growth Factor beta
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Adenosine Triphosphate
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases