Abstract
The discovery and optimization of a novel series of aminoisoquinolines as potent, selective, and efficacious inhibitors of the mutant B-Raf pathway is presented. The N-linked pyridylpyrimidine benzamide 2 was identified as a potent, modestly selective inhibitor of the B-Raf enzyme. Replacement of the benzamide with an aminoisoquinoline core significantly improved kinase selectivity and imparted favorable pharmacokinetic properties, leading to the identification of 1 as a potent antitumor agent in xenograft models.
MeSH terms
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Administration, Oral
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Animals
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Biological Availability
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Cell Line, Tumor
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Drug Discovery
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Humans
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Isoquinolines / administration & dosage
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Isoquinolines / chemical synthesis
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Isoquinolines / pharmacokinetics*
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Isoquinolines / pharmacology*
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MAP Kinase Signaling System / drug effects*
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Male
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Mice
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Models, Molecular
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Molecular Conformation
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Mutant Proteins / antagonists & inhibitors*
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Mutant Proteins / chemistry
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Mutant Proteins / genetics
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Mutant Proteins / metabolism
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Mutation*
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
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Proto-Oncogene Proteins B-raf / chemistry
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins B-raf / metabolism
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Rats
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Substrate Specificity
Substances
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Isoquinolines
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Mutant Proteins
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins B-raf
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1-aminoisoquinoline