Open AccessIdentification of a new JNK inhibitor targeting the JNK-JIP interaction site
Author(s) -
John L. Stebbins,
Surya K. De,
Thomas Machleidt,
Barbara Becattini,
Jesús Vázquez,
Christian Kuntzen,
Li-Hsing Chen,
Jason Cellitti,
Megan Riel-Mehan,
Aras Emdadi,
Giovanni Solinas,
Michael Karin,
Maurizio Pellecchia
Publication year - 2008
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0805677105
Subject(s) - kinase , scaffold protein , microbiology and biotechnology , phosphorylation , protein kinase a , docking (animal) , in vitro , biology , signal transduction , chemistry , biochemistry , medicine , nursing
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 bothin 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 bothin vitro andin 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 andin vivo , BI-78D3 represents not only a JNK inhibitor, but also a promising stepping stone toward the development of an innovative class of therapeutics.