Abstract
c-Met is a transmembrane tyrosine kinase that mediates activation of several signaling pathways implicated in aggressive cancer phenotypes. In recent years, research into this area has highlighted c-Met as an attractive cancer drug target, triggering a number of approaches to disrupt aberrant c-Met signaling. Screening efforts identified a unique class of 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one kinase inhibitors, exemplified by 1. Subsequent SAR studies led to the development of 81 (MK-2461), a potent inhibitor of c-Met that was efficacious in preclinical animal models of tumor suppression. In addition, biochemical studies and X-ray analysis have revealed that this unique class of kinase inhibitors binds preferentially to the activated (phosphorylated) form of the kinase. This report details the development of 81 and provides a description of its unique biochemical properties.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Benzocycloheptenes / chemical synthesis*
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Benzocycloheptenes / pharmacokinetics
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Benzocycloheptenes / pharmacology
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Cell Line, Tumor
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Crystallography, X-Ray
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Dogs
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Drug Screening Assays, Antitumor
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Female
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Haplorhini
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Humans
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Mice
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Mice, Nude
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Models, Molecular
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Mutation
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Neoplasm Transplantation
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Phosphorylation
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Protein Binding
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Pyrazoles / chemical synthesis
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology
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Pyridines / chemical synthesis*
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Pyridines / pharmacokinetics
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Pyridines / pharmacology
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Rats
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / genetics
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology
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Transplantation, Heterologous
Substances
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5H-benzo(4,5)cyclohepta(1,2-b)pyridin-5-one
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Antineoplastic Agents
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Benzocycloheptenes
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Pyrazoles
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Pyridines
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Sulfonamides
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RON protein
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Receptor Protein-Tyrosine Kinases