Abstract
VEGFR-2, TIE-2, and EphB4 are essential for both angiogenesis and tumorigenesis. Herein, we designed and prepared three classes of multi-target inhibitors based on the extensive sequence homology along the kinase domain of angiogenic RTKs. Biological evaluation indicated that these multi-target inhibitors exhibited considerable potential as novel anti-angiogeneic and anticancer agents. Among them, a diaryl thiourea bearing 1H-indazole-3-amine (16a) displayed the most potent RTK inhibition and excellent selectivity. It also showed inhibition on viability of human umbilical vein endothelial cells and anti-proliferation against a broad spectrum of cancer cells. Therefore, 1H-indazole-3-amine could serve as a promising hinge binding group for multi-target inhibitors of VEGFR-2, Tie-2, and EphB4.
Keywords:
1H-indazol-3-amine; Anti-angiogenesis agents; Hinge-binding group; Multi-target; RTK inhibitors.
Copyright © 2017 Elsevier Masson SAS. All rights reserved.
MeSH terms
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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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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Drug Discovery*
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Drug Screening Assays, Antitumor
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Human Umbilical Vein Endothelial Cells / drug effects
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Humans
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Indazoles / chemistry
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Indazoles / pharmacology*
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Molecular Docking Simulation
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Molecular Structure
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Neovascularization, Pathologic / drug therapy*
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Neovascularization, Pathologic / metabolism
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Neovascularization, Pathologic / pathology
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / metabolism
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Structure-Activity Relationship
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Thiourea / chemical synthesis
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Thiourea / chemistry
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Thiourea / pharmacology*
Substances
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1H-indazol-3-amine
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Angiogenesis Inhibitors
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Antineoplastic Agents
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Indazoles
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Protein Kinase Inhibitors
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Receptor Protein-Tyrosine Kinases
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Thiourea