Hit-to-lead optimization and kinase selectivity of imidazo[1,2-a]quinoxalin-4-amine derived JNK1 inhibitors
Copyright policy )Hit-to-lead optimization and kinase selectivity of imidazo[1,2-a]quinoxalin-4-amine derived JNK1 inhibitors
As the result of a rhJNK1 HTS, the imidazo[1,2-a]quinoxaline 1 was identified as a 1.6 μM rhJNK1 inhibitor. Optimization of this compound lead to AX13587 (rhJNK1 IC50=160 nM) which was co-crystallized with JNK1 to identify key molecular interactions. Kinase profiling against 125+ kinases revealed AX13587 was an inhibitor of JNK, MAST3, and MAST4 whereas its methylene homolog AX14373 (native JNK1 IC50=47 nM) was a highly specific JNK inhibitor.
- Torrey Pines Institute For Molecular Studies United States
Models, Molecular, Dose-Response Relationship, Drug, Molecular Structure, Imidazoles, Crystallography, X-Ray, Recombinant Proteins, Structure-Activity Relationship, Catalytic Domain, Quinoxalines, Humans, Mitogen-Activated Protein Kinase 8, Protein Kinase Inhibitors
Models, Molecular, Dose-Response Relationship, Drug, Molecular Structure, Imidazoles, Crystallography, X-Ray, Recombinant Proteins, Structure-Activity Relationship, Catalytic Domain, Quinoxalines, Humans, Mitogen-Activated Protein Kinase 8, Protein Kinase Inhibitors
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