The identification of novel p38α isoform selective kinase inhibitors having an unprecedented p38α binding mode

Bioorg Med Chem Lett. 2013 Jul 15;23(14):4120-6. doi: 10.1016/j.bmcl.2013.05.047. Epub 2013 May 23.

Abstract

A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38β isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed.

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Humans
  • Hydrogen Bonding
  • Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 14 / metabolism
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Structure, Tertiary
  • Structure-Activity Relationship

Substances

  • Protein Isoforms
  • Protein Kinase Inhibitors
  • Mitogen-Activated Protein Kinase 14