X-ray crystal structure of JNK2 complexed with the p38alpha inhibitor BIRB796: insights into the rational design of DFG-out binding MAP kinase inhibitors

Bioorg Med Chem Lett. 2010 Sep 1;20(17):5217-20. doi: 10.1016/j.bmcl.2010.06.157. Epub 2010 Jul 23.

Abstract

JNK2 and p38alpha are closely related mitogen-activated protein kinases that regulate various cellular activities and are considered drug targets for inflammatory diseases. We have determined the X-ray crystal structure of the clinical phase II p38alpha inhibitor BIRB796 bound to its off-target JNK2. This shows for the first time a JNK subfamily member in the DFG-out conformation. The fully resolved activation loop reveals that BIRB796 inhibits JNK2 activation by stabilizing the loop in a position that does not allow its phosphorylation by upstream kinases. The structure suggests that substituents at the BIRB796 morpholino group and modifications of the t-butyl moiety should further increase the p38alpha to JNK2 potency ratio. For the design of selective DFG-out binding JNK2 inhibitors, the binding pocket of the BIRB796 tolyl group may have the best potential.

MeSH terms

  • Crystallography, X-Ray
  • Drug Design
  • Mitogen-Activated Protein Kinase 9 / chemistry*
  • Mitogen-Activated Protein Kinases / chemistry*
  • Models, Molecular
  • Molecular Structure
  • Naphthalenes / chemistry*
  • Protein Kinase Inhibitors / chemistry*
  • Pyrazoles / chemistry*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*

Substances

  • Naphthalenes
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Mitogen-Activated Protein Kinase 9
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • doramapimod