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

Journal article
Authors John L. Stebbins
Surya K. De
Thomas Machleidt
Barbara Becattini
Jesus Vazquez
Christian Kuntzen
Li-Hsing Chen
Jason F. Cellitti
Megan Riel-Mehan
Aras Emdadi
Giovanni Solinas
Michael Karin
Maurizio Pellecchia
Published in Proceedings of the National Academy of Science of the United States of America
Volume 105
Issue 43
Pages 16809–16813
ISSN 0027-8424
Publication year 2008
Published at Wallenberg Laboratory
Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 16809–16813
Language en
Keywords Diabetes, Insulin Resistance, JNK
Subject categories Basic Medicine


NK 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.

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