Hit-to-lead optimization and kinase selectivity of imidazo[1,2-a]quinoxalin-4-amine derived JNK1 inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 18; pp. 5217 - 5222
• Main Authors: Li, Bei, Cociorva, Oana M., Nomanbhoy, Tyzoon, Weissig, Helge, Li, Qiang, Nakamura, Kai, Liyanage, Marek, Zhang, Melissa C., Shih, Ann Y., Aban, Arwin, Hu, Yi, Cajica, Julia, Pham, Lan, Kozarich, John W., Shreder, Kevin R.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-09-2013
• Subjects: amino acid derivatives; AX13587; AX14373; Catalytic Domain - drug effects; chemistry; Crystallography, X-Ray; Dose-Response Relationship, Drug; enzyme inhibitors; Humans; Imidazo[1,2-a]quinoxalin-4-amine; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; JNK1 inhibitor; Kinase profiling; mitogen-activated protein kinase; Mitogen-Activated Protein Kinase 8 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 8 - metabolism; Models, Molecular; Molecular Structure; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Quinoxalines - chemical synthesis; Quinoxalines - chemistry; Quinoxalines - pharmacology; Recombinant Proteins - metabolism; Structure-Activity Relationship; system optimization; Imidazo[1,2-a]quinoxalin-4-amine; JNK1 inhibitor; AX13587; Kinase profiling; AX14373
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.06.087

As the result of a rhJNK1 HTS, the imidazo[1,2-a]quinoxaline 1 was identified as a 1.6μM rhJNK1 inhibitor. Optimization of this compound lead to AX13587 (rhJNK1 IC50=160nM) 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=47nM) was a highly specific JNK inhibitor.