The structural basis for the specificity of pyridinylimidazole inhibitors of p38 MAP kinase

Chem Biol. 1997 Jun;4(6):423-31. doi: 10.1016/s1074-5521(97)90194-0.

Abstract

Background: The p38 mitogen-activated protein (MAP) kinase regulates signal transduction in response to environmental stress. Pyridinylimidazole compounds are specific inhibitors of p38 MAP kinase that block the production of the cytokines interleukin-1beta and tumor necrosis factor alpha, and they are effective in animal models of arthritis, bone resorption and endotoxin shock. These compounds have been useful probes for studying the physiological functions of the p38-mediated MAP kinase pathway.

Results: We report the crystal structure of a novel pyridinylimidazole compound complexed with p38 MAP kinase, and we demonstrate that this compound binds to the same site on the kinase as does ATP. Mutagenesis showed that a single residue difference between p38 MAP kinase and other MAP kinases is sufficient to confer selectivity among pyridinylimidazole compounds.

Conclusions: Our results reveal how pyridinylimidazole compounds are potent and selective inhibitors of p38 MAP kinase but not other MAP kinases. It should now be possible to design other specific inhibitors of activated p38 MAP kinase using the structure of the nonphosphorylated enzyme.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Binding Sites
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors*
  • Calcium-Calmodulin-Dependent Protein Kinases / chemistry
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / metabolism
  • Imidazoles / pharmacology
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinases*
  • Models, Molecular
  • Molecular Structure
  • Mutation
  • Protein Binding
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / metabolism
  • Pyridines / pharmacology
  • Structure-Activity Relationship
  • p38 Mitogen-Activated Protein Kinases

Substances

  • 4-(4-fluorophenyl)-1-(4-piperidinyl)-5-(4-pyridyl)-imidazole
  • Enzyme Inhibitors
  • Imidazoles
  • Pyridines
  • Adenosine Triphosphate
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580
  • 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole