Abstract
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.
Keywords:
AX13587; AX14373; Imidazo[1,2-a]quinoxalin-4-amine; JNK1 inhibitor; Kinase profiling.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Catalytic Domain / drug effects
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Crystallography, X-Ray
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Dose-Response Relationship, Drug
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Humans
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Imidazoles / chemical synthesis
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Imidazoles / chemistry
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Imidazoles / pharmacology*
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Mitogen-Activated Protein Kinase 8 / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase 8 / metabolism
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Models, Molecular
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Molecular Structure
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Quinoxalines / chemical synthesis
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Quinoxalines / chemistry
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Quinoxalines / pharmacology*
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Recombinant Proteins / metabolism
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Structure-Activity Relationship
Substances
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Imidazoles
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Protein Kinase Inhibitors
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Quinoxalines
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Recombinant Proteins
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imidazo(1,2-a)quinoxalin-4-amine
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Mitogen-Activated Protein Kinase 8