Abstract
An amide library derived from the pyrrolo[2,1-f][1,2,4]triazine scaffold led to the identification of modest inhibitors of Met kinase activity. Introduction of polar side chains at C-6 of the pyrrolotriazine core provided significant improvements in in vitro potency. The amide moiety could be replaced with acylurea and malonamide substituents to give compounds with improved potency in the Met-driven GTL-16 human gastric carcinoma cell line. Acylurea pyrrolotriazines with substitution at C-5 demonstrated single digit nanomolar kinase activity. X-ray crystallography revealed that the C-5 substituted pyrrolotriazines bind to the Met kinase domain in an ATP-competitive manner.
MeSH terms
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Animals
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Caco-2 Cells / drug effects
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Cell Proliferation / drug effects
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Cells, Cultured / drug effects
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Crystallography, X-Ray
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology*
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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Glutathione Transferase / antagonists & inhibitors
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Humans
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Mice
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Molecular Structure
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Protein Conformation
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-met
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Pyrroles / chemistry*
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptors, Growth Factor / antagonists & inhibitors*
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Receptors, Growth Factor / metabolism
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Stomach Neoplasms / blood
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Stomach Neoplasms / drug therapy*
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Stomach Neoplasms / enzymology
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Structure-Activity Relationship
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Triazines / chemistry*
Substances
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Enzyme Inhibitors
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Ether-A-Go-Go Potassium Channels
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KCNH1 protein, human
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Proto-Oncogene Proteins
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Pyrroles
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Receptors, Growth Factor
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Triazines
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Glutathione Transferase
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MET protein, human
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Proto-Oncogene Proteins c-met
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RON protein
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Receptor Protein-Tyrosine Kinases