Abstract
In our continued efforts to search for potent and novel receptor tyrosine kinase (RTK) inhibitors as potential anticancer agents, we discovered, through a structure-based design, that 3-aminoindazole could serve as an efficient hinge-binding template for kinase inhibitors. By incorporating an N,N'-diaryl urea moiety at the C4-position of 3-aminodazole, a series of RTK inhibitors were generated, which potently inhibited the tyrosine kinase activity of the vascular endothelial growth factor receptor and the platelet-derived growth factor receptor families. A number of compounds with potent oral activity were identified by utilizing an estradiol-induced mouse uterine edema model and an HT1080 human fibrosarcoma xenograft tumor model. In particular, compound 17p (ABT-869) was found to possess favorable pharmacokinetic profiles across different species and display significant tumor growth inhibition in multiple preclinical animal models.
MeSH terms
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Adenosine Triphosphate / chemistry
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Administration, Oral
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Angiogenesis Inhibitors / chemical synthesis*
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Angiogenesis Inhibitors / chemistry
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Angiogenesis Inhibitors / pharmacology
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Animals
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Binding Sites
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Edema / chemically induced
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Edema / pathology
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Estradiol
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Female
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Humans
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Hydrophobic and Hydrophilic Interactions
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Indazoles / chemical synthesis*
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Indazoles / chemistry
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Indazoles / pharmacology
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Male
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Mice
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Models, Molecular
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NIH 3T3 Cells
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Phenylurea Compounds / chemical synthesis*
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Phenylurea Compounds / chemistry
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Phenylurea Compounds / pharmacology
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Phosphorylation
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / chemistry
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Receptor Protein-Tyrosine Kinases / metabolism
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Structure-Activity Relationship
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Uterus / drug effects
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Uterus / pathology
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Xenograft Model Antitumor Assays
Substances
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Angiogenesis Inhibitors
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Indazoles
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Phenylurea Compounds
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Estradiol
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Adenosine Triphosphate
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linifanib
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Receptor Protein-Tyrosine Kinases