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

Autor:	Kai Nakamura, Qiang Li, Tyzoon K. Nomanbhoy, Ann Yu-Jung Shih, Helge Weissig, Oana Cociorva, Lan Pham, John W. Kozarich, Yi Hu, Melissa C. Zhang, Marek Liyanage, Julia Cajica, Kevin R. Shreder, Arwin Aban, Bei Li
Rok vydání:	2013
Předmět:	Models Molecular Stereochemistry Clinical Biochemistry Pharmaceutical Science Crystallography X-Ray Biochemistry chemistry.chemical_compound Structure-Activity Relationship Quinoxaline Catalytic Domain Quinoxalines Drug Discovery Humans Mitogen-Activated Protein Kinase 8 Methylene Molecular Biology Protein Kinase Inhibitors Molecular interactions Dose-Response Relationship Drug Molecular Structure Kinase Organic Chemistry Imidazoles Hit to lead Jnk inhibitor Recombinant Proteins chemistry Molecular Medicine Amine gas treating Selectivity
Zdroj:	Bioorganicmedicinal chemistry letters. 23(18)
ISSN:	1464-3405
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a7b642fbafafceb853661bc276b0d062 https://pubmed.ncbi.nlm.nih.gov/23916259 Zobrazit plný text záznamu Full Text from ScienceDirect