1032262-52-4Relevant academic research and scientific papers
Design and characterization of a potent and selective dual ATP- and substrate-competitive subnanomolar bidentate c-Jun N-terminal kinase (JNK) inhibitor
Stebbins, John L.,De, Surya K.,Pavlickova, Petra,Chen, Vida,MacHleidt, Thomas,Chen, Li-Hsing,Kuntzen, Christian,Kitada, Shinichi,Karin, Michael,Pellecchia, Maurizio
experimental part, p. 6206 - 6214 (2011/11/06)
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 (IC50 = 18 nM; K i = 1.5 nM) and JNK/substrate association in a displacement assay (IC50 = 46 nM; Ki = 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.
BI-DENTATE COMPOUNDS AS KINASE INHIBITORS
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Page/Page column 24, (2009/03/07)
The present invention provides compound having the general structure A or pharmaceutically acceptable salts thereof: Het-L-P (A) wherein Het is an aromatic moiety comprising a heterocyclic structure mimicking ATP, P is a docking site derived peptide or a
Development of paramagnetic probes for molecular recognition studies in protein kinases
Vazquez, Jesus,De, Surya K.,Chen, Li-Hsing,Riel-Mehan, Megan,Emdadi, Aras,Cellitti, Jason,Stebbins, John L.,Rega, Michele F.,Pellecchia, Maurizio
experimental part, p. 3460 - 3465 (2009/04/07)
We report on the synthesis and evaluation of an indazole-spin-labeled compound that was designed as an effective chemical probe for second site screening against the protein kinase JNK using NMR-based techniques. We demonstrate the utility of the derived compound in detecting and characterizing binding events at the protein kinase docking site. In addition, we report on the NMR-based design and synthesis of a bidentate compound spanning both the ATP site and the docking site. We show that the resulting compound has nanomolar affinity for JNK despite the relatively weak affinities of the individual fragments that constitute it. The approach demonstrates that targeting the docking site of protein kinases represents a valuable yet unexplored avenue to obtain potent kinase inhibitors with increased selectivity.
