Publication: Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach
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0
Issued Date
2013
Resource Type
File Type
application/pdf
ISSN
0960894X
Other identifier(s)
2-s2.0-84876669366
Rights Holder(s)
มหาวิทยาลัยศรีนครินทรวิโรฒ
Bibliographic Citation
Bioorganic and Medicinal Chemistry Letters. Vol 23, No.10 (2013), p.2962-2967
Suggested Citation
Sanphanya K., Wattanapitayakul S.K., Phowichit S., Fokin V.V., Vajragupta O. Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach. Bioorganic and Medicinal Chemistry Letters. Vol 23, No.10 (2013), p.2962-2967. doi:10.1016/j.bmcl.2013.03.042 Retrieved from: https://hdl.handle.net/20.500.14740/6658
Abstract
We report a novel VEGFR-2 inhibitor, developed by the back-to-front approach. Docking experiments indicated that the 3-chloromethylphenylurea motif of the lead compound occupied the back pocket of VEGFR-2 kinase. An attempt was made to enhance the binding affinity of 1 by expanding the structure to access the front pocket using a triazole linker. A library of 1,4-(disubstituted)-1H-1, 2,3-triazoles were screened in silico, and one compound (VH02) was identified with an IC50 against VEGFR-2 of 0.56 μM. VH02 showed antiangiogenic effects, inhibiting tube formation in HUVEC cells (EA.hy926) at 0.3 μM, 13 times lower than its cytotoxic dose. These enzymatic and cellular activities suggest that VH02 has potential as a lead for further optimization. © 2013 Elsevier Ltd. All rights reserved.
Subject(s)
6 indazolyl triazole derivative
Angiogenesis inhibitor
Antineoplastic agent
Sorafenib
Triazole
Unclassified drug
Vasculotropin receptor 2
Antiangiogenic activity
Antineoplastic activity
Article
Binding affinity
Binding site
Cancer cell culture
Controlled study
Cytotoxicity
Drug structure
Enzyme active site
Enzyme activity
Human
Human cell
Hydrogen bond
Molecular docking
Protein phosphorylation
Antineoplastic Agents
Cell Line, Tumor
Cell Proliferation
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Hep G2 Cells
Human Umbilical Vein Endothelial Cells
Humans
Indazoles
MCF-7 Cells
Models, Molecular
Molecular Structure
Phenylurea Compounds
Protein Kinase Inhibitors
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2
Angiogenesis inhibitor
Antineoplastic agent
Sorafenib
Triazole
Unclassified drug
Vasculotropin receptor 2
Antiangiogenic activity
Antineoplastic activity
Article
Binding affinity
Binding site
Cancer cell culture
Controlled study
Cytotoxicity
Drug structure
Enzyme active site
Enzyme activity
Human
Human cell
Hydrogen bond
Molecular docking
Protein phosphorylation
Antineoplastic Agents
Cell Line, Tumor
Cell Proliferation
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Hep G2 Cells
Human Umbilical Vein Endothelial Cells
Humans
Indazoles
MCF-7 Cells
Models, Molecular
Molecular Structure
Phenylurea Compounds
Protein Kinase Inhibitors
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2