Hit-to-lead optimization and kinase selectivity of imidazo[1,2-a]quinoxalin-4-amine derived JNK1 inhibitors |
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Authors: | Bei Li Oana M Cociorva Tyzoon Nomanbhoy Helge Weissig Qiang Li Kai Nakamura Marek Liyanage Melissa C Zhang Ann Y Shih Arwin Aban Yi Hu Julia Cajica Lan Pham John W Kozarich Kevin R Shreder |
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Institution: | ActivX Biosciences, Inc., 11025 N. Torrey Pines Road, La Jolla, CA 92037, USA |
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Abstract: | As the result of a rhJNK1 HTS, the imidazo1,2-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. |
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Keywords: | JNK1 inhibitor Kinase profiling |
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