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

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