Abstract
A series of isoxazolo[3,4-b]quinoline-3,4(1H,9H)-diones were synthesized as potent inhibitors against Pim-1 and Pim-2 kinases. The structure-activity-relationship studies started from a high-throughput screening hit and was guided by molecular modeling of inhibitors in the active site of Pim-1 kinase. Installing a hydroxyl group on the benzene ring of the core has the potential to form a key hydrogen bond interaction to the hinge region of the binding pocket and thus resulted in the most potent inhibitor, 19, with K(i) values at 2.5 and 43.5 nM against Pim-1 and Pim-2, respectively. Compound 19 also exhibited an activity profile with a high degree of kinase selectivity.
MeSH terms
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Combinatorial Chemistry Techniques
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Crystallography, X-Ray
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Humans
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Isoxazoles / chemical synthesis*
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Isoxazoles / chemistry
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Isoxazoles / pharmacology*
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Models, Molecular*
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Molecular Conformation
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Molecular Structure
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
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Quinolines / chemical synthesis*
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Quinolines / chemistry
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Quinolines / pharmacology*
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Structure-Activity Relationship
Substances
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Isoxazoles
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PIM2 protein, human
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Proto-Oncogene Proteins
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Quinolines
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PIM1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-pim-1