Discovery of novel dual VEGFR2 and Src inhibitors using a multistep virtual screening approach

Simultaneous inhibition of VEGFR2 and Src may enhance the efficacy of VEGFR2-targeted cancer therapeutics. Hence, development of dual inhibitors on VEGFR2 and Src can be a useful strategy for such treatments. A multistep virtual screening protocol, comprising ligand-based support vector machines met...

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Bibliographic Details
Published in:Future medicinal chemistry 2017-01, Vol.9 (1), p.7-24
Main Authors: Chen, Shangying, Qin, Chu, Sin, Jia En, Yang, Xuan, Tao, Lin, Zeng, Xian, Zhang, Peng, Gao, Chun Mei, Jiang, Yu Yang, Zhang, Cheng, Chen, Yu Zong, Chui, Wai Keung
Format: Article
Language:English
Subjects:
2-amino-3-cyanopyridines
cancer
Cell Line, Tumor
combinatorial support vector machines
drug discovery
Drug Evaluation, Preclinical - methods
Humans
Models, Molecular
molecular docking
Molecular Structure
multikinase inhibitors
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Src
src-Family Kinases - antagonists & inhibitors
src-Family Kinases - metabolism
Structure-Activity Relationship
Surflex-Dock
Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-2 - metabolism
VEGFR2
virtual screening
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Summary:Simultaneous inhibition of VEGFR2 and Src may enhance the efficacy of VEGFR2-targeted cancer therapeutics. Hence, development of dual inhibitors on VEGFR2 and Src can be a useful strategy for such treatments. A multistep virtual screening protocol, comprising ligand-based support vector machines method, drug-likeness rules filter and structure-based molecular docking, was developed and employed to identify dual inhibitors of VEGFR2 and Src from a large commercial chemical library. Kinase inhibitory assays and cell viability assays were then used for experimental validation. A set of compounds belonging to six different molecular scaffolds was identified and sent for biological evaluation. Compound belonging to the 2-amino-3-cyanopyridine scaffold exhibited good antiproliferative effect and dual-target activities against VEGFR2 and Src. This study demonstrated the ability of the multistep virtual screening approach to identify novel multitarget agents.
ISSN:1756-8919
1756-8927
DOI:10.4155/fmc-2016-0162