Abstract
Inspired by that the multi-target inhibitors against receptor tyrosine kinases (RTKs) have significantly improved the effect of clinical treatment for cancer, and based on the chemical structure of Linifanib (ABT-869, Abbott), two series of diaryl-ureas with novel isoxazol[3,4-b]pyridine-3-amino-structure were designed and synthesized as multi-target inhibitors against RTKs. The preliminary biological evaluation showed that several compounds exhibited comparable potency with Linifanib. Compound S21 was identified as the most potent inhibitor against Fms-like tyrosine kinase 3 (FLT-3), kinase insert domain containing receptor (KDR) and platelet-derived growth factor receptor β (PDGFR-β) with its IC50 values were 4 nM, 3 nM and 8 nM respectively, it also showed potent inhibitory activities against several cancer cells.
Keywords:
Antiangiogenesis; FLT3; KDR; Multi-target inhibitors; PDGFR-β; Receptor tyrosine kinase.
Copyright © 2018 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Binding Sites
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Cell Line
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Cell Proliferation / drug effects
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Drug Design*
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Humans
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Molecular Docking Simulation
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacology
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Protein Structure, Tertiary
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Pyridines / chemistry*
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
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Receptor Protein-Tyrosine Kinases / metabolism*
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Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors
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Structure-Activity Relationship
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Urea / chemistry*
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Urea / pharmacology
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
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fms-Like Tyrosine Kinase 3 / antagonists & inhibitors
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fms-Like Tyrosine Kinase 3 / metabolism
Substances
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Protein Kinase Inhibitors
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Pyridines
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Urea
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Receptor Protein-Tyrosine Kinases
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Receptor, Platelet-Derived Growth Factor beta
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Vascular Endothelial Growth Factor Receptor-2
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fms-Like Tyrosine Kinase 3