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Protein–protein Interactions

Getting rid of JNK

Nature Reviews Drug Discovery volume 7, page 975 (2008)Cite this article

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The scaffolding protein JIP1 enhances JNK signalling by bringing JNK into proximity with its upstream kinases and substrates. Previous studies have demonstrated that expression of the JNK-binding domain of JIP1 acts as a competitive inhibitor of JNK signalling and restores normoglycaemia in a mouse model of type 2 diabetes. In this study, the authors screened 30,000 compounds for the ability to disrupt the interaction between JNK and JIP1 without causing cytotoxicity. They identified BI-78D3 as a potent inhibitor of this interaction and of JNK activity by using the DELFIA assay (dissociation enhanced lanthanide fluorescent immunoassay) and a time-resolved fluorescence energy transfer based kinase assay.

BI-78D3 displaced biotinylated JIP1 from GST-JNK1 and selectively inhibited JNK activity at nanomolar concentrations. Further characterization of the docked structure of BI-78D3 onto JNK1 revealed that the compound's benzodioxan, nitro and thiazole moieties are key to its inhibitory activity. Moreover, the interaction between BI-78D3 and JNK1 seems to be dependent on JNK R127, a residue that is known to be required for JIP1 binding, and C167.

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ORIGINAL RESEARCH PAPER

  1. Stebbins, J. L. et al. Identification of a new JNK inhibitor targeting the JNK–JIP interaction site. Proc. Natl Acad. Sci. USA 105, 16809–16813 (2008)

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Authors
  1. Monica Hoyos Flight
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Flight, M. Getting rid of JNK. Nat Rev Drug Discov 7, 975 (2008). https://doi.org/10.1038/nrd2771

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