Identification of a new JNK inhibitor targeting the JNK-JIP interaction site

Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16809-13. doi: 10.1073/pnas.0805677105. Epub 2008 Oct 15.

Abstract

JNK is a stress-activated protein kinase that modulates pathways implicated in a variety of disease states. JNK-interacting protein-1 (JIP1) is a scaffolding protein that enhances JNK signaling by creating a proximity effect between JNK and upstream kinases. A minimal peptide region derived from JIP1 is able to inhibit JNK activity both in vitro and in cell. We report here a series of small molecules JIP1 mimics that function as substrate competitive inhibitors of JNK. One such compound, BI-78D3, dose-dependently inhibits the phosphorylation of JNK substrates both in vitro and in cell. In animal studies, BI-78D3 not only blocks JNK dependent Con A-induced liver damage but also restores insulin sensitivity in mouse models of type 2 diabetes. Our findings open the way for the development of protein kinase inhibitors targeting substrate specific docking sites, rather than the highly conserved ATP binding sites. In view of its favorable inhibition profile, selectivity, and ability to function in the cellular milieu and in vivo, BI-78D3 represents not only a JNK inhibitor, but also a promising stepping stone toward the development of an innovative class of therapeutics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Binding, Competitive
  • Chemical and Drug Induced Liver Injury
  • Diabetes Mellitus, Experimental / drug therapy
  • Dioxanes / pharmacology*
  • Insulin Resistance
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Liver Diseases / prevention & control
  • Mice
  • Molecular Mimicry
  • Phosphorylation / drug effects
  • Protein Binding
  • Protein Kinase Inhibitors / pharmacology*
  • Signal Transduction
  • Thiazoles / pharmacology*

Substances

  • 4-(2,3-dihydro-1,4-benzodioxin-6-yl)-2,4-dihydro-5-((5-nitro-2-thiazolyl)thio)-3H-1,2,4-triazol-3-one
  • Adaptor Proteins, Signal Transducing
  • Dioxanes
  • MAPK8IP1 protein, human
  • Protein Kinase Inhibitors
  • Thiazoles
  • JNK Mitogen-Activated Protein Kinases