Design and characterization of a potent and selective dual ATP- and substrate-competitive subnanomolar bidentate c-Jun N-terminal kinase (JNK) inhibitor.

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Stebbins JL, De SK, Pavlickova P, Chen V, Machleidt T, Chen LH, Kuntzen C, Kitada S, Karin M, Pellecchia M

Design and characterization of a potent and selective dual ATP- and substrate-competitive subnanomolar bidentate c-Jun N-terminal kinase (JNK) inhibitor.

J Med Chem. 2011 Sep 22;54(18):6206-14. doi: 10.1021/jm200479c. Epub 2011 Aug 23.

PubMed ID

21815634 [ View in PubMed

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Abstract

c-Jun N-terminal kinases (JNKs) represent valuable targets in the development of new therapies. Present on the surface of JNK is a binding pocket for substrates and the scaffolding protein JIP1 in close proximity to the ATP binding pocket. We propose that bidentate compounds linking the binding energies of weakly interacting ATP and substrate mimetics could result in potent and selective JNK inhibitors. We describe here a bidentate molecule, 19, designed against JNK. 19 inhibits JNK kinase activity (IC(50) = 18 nM; K(i) = 1.5 nM) and JNK/substrate association in a displacement assay (IC(50) = 46 nM; K(i) = 2 nM). Our data demonstrate that 19 targets for the ATP and substrate-binding sites on JNK concurrently. Finally, compound 19 successfully inhibits JNK in a variety of cell-based experiments, as well as in vivo where it is shown to protect against Jo-2 induced liver damage and improve glucose tolerance in diabetic mice.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Pyrazolanthrone	Mitogen-activated protein kinase 8	IC 50 (nM)	14000	N/A	N/A	Details