PUBLICATION
Design, synthesis and biological evaluation of indazole derivatives as VEGFR-2 kinase inhibitors with anti-angiogenic properties
- Authors
- Zha, H., Li, F., Cai, L., Liu, W., Zhang, M., Gu, S., Feng, H., Xia, Z., Guo, C., Wu, X., Li, C., Zhu, S., Li, R., Shi, J., Liu, X.
- ID
- ZDB-PUB-241004-3
- Date
- 2024
- Source
- European Journal of Medicinal Chemistry 279: 116889 (Journal)
- Registered Authors
- Keywords
- Anti-angiogenic, Indazole derivatives, VEGFR-2, Zebrafish
- MeSH Terms
-
- Angiogenesis Inhibitors*/chemical synthesis
- Angiogenesis Inhibitors*/chemistry
- Angiogenesis Inhibitors*/pharmacology
- Animals
- Cell Movement*/drug effects
- Cell Proliferation/drug effects
- Dose-Response Relationship, Drug
- Drug Design*
- Human Umbilical Vein Endothelial Cells*/drug effects
- Humans
- Indazoles*/chemical synthesis
- Indazoles*/chemistry
- Indazoles*/pharmacology
- Mice
- Molecular Structure
- Protein Kinase Inhibitors*/chemical synthesis
- Protein Kinase Inhibitors*/chemistry
- Protein Kinase Inhibitors*/pharmacology
- Structure-Activity Relationship
- Vascular Endothelial Growth Factor Receptor-2*/antagonists & inhibitors
- Vascular Endothelial Growth Factor Receptor-2*/metabolism
- Zebrafish*
- PubMed
- 39353237 Full text @ Eur. J. Med. Chem.
Citation
Zha, H., Li, F., Cai, L., Liu, W., Zhang, M., Gu, S., Feng, H., Xia, Z., Guo, C., Wu, X., Li, C., Zhu, S., Li, R., Shi, J., Liu, X. (2024) Design, synthesis and biological evaluation of indazole derivatives as VEGFR-2 kinase inhibitors with anti-angiogenic properties. European Journal of Medicinal Chemistry. 279:116889.
Abstract
The strategy of inhibiting angiogenesis, specifically by targeting vascular endothelial growth factor receptor 2 (VEGFR-2), has been proven effective in tumor treatment. In this study, we designed several VEGFR-2 kinase inhibitors based on an indazole scaffold. Among them, the most potent compound, 30, inhibits VEGFR-2 (IC50 = 1.24 nM) with subtle selectivity over other kinases. It demonstrates significant inhibitory activity against HUVEC angiogenesis and inhibits cell migration in a dose-dependent manner. Additionally, it exhibits low acute toxicity in mice. In vivo studies, compound 30 demonstrates favorable pharmacokinetic profiles. It suppresses tumor angiogenesis in the zebrafish subintestinal vessel model, indicating that it may be a potential angiogenesis inhibitor for further development.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping