PUBLICATION
SKLB610: A Novel Potential Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases Inhibits Angiogenesis and Tumor Growth in Vivo
- Authors
- Cao, Z.X., Zheng, R.L., Lin, H.J., Luo, S.D., Zhou, Y., Xu, Y.Z., Zeng, X.X., Wang, Z., Zhou, L.N., Mao, Y.Q., Yang, L., Wei, Y.Q., Yu, L.T., Yang, S.Y., and Zhao, Y.L.
- ID
- ZDB-PUB-110629-19
- Date
- 2011
- Source
- Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 27(5): 565-574 (Journal)
- Registered Authors
- Keywords
- SKLB610, vascular endothelial growth factor receptor, angiogenesis, tumor growth
- MeSH Terms
-
- Amides/chemical synthesis
- Amides/pharmacology
- Angiogenesis Inhibitors/chemical synthesis
- Angiogenesis Inhibitors/pharmacology*
- Animals
- Carcinoma, Non-Small-Cell Lung/drug therapy*
- Carcinoma, Non-Small-Cell Lung/metabolism
- Carcinoma, Non-Small-Cell Lung/pathology
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Collagen/metabolism
- Colorectal Neoplasms/drug therapy*
- Colorectal Neoplasms/metabolism
- Colorectal Neoplasms/pathology
- Drug Combinations
- Endothelial Cells/cytology
- Endothelial Cells/drug effects
- Female
- Humans
- Laminin/metabolism
- Mice
- Mice, Nude
- Mitogen-Activated Protein Kinase 1/antagonists & inhibitors*
- Mitogen-Activated Protein Kinase 1/metabolism
- Neovascularization, Pathologic/drug therapy*
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Phosphorylation/drug effects
- Picolinic Acids/chemical synthesis
- Picolinic Acids/pharmacology*
- Protein Kinase Inhibitors/chemical synthesis
- Protein Kinase Inhibitors/pharmacology
- Proteoglycans/metabolism
- Receptor, Fibroblast Growth Factor, Type 2/antagonists & inhibitors*
- Receptor, Fibroblast Growth Factor, Type 2/metabolism
- Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors*
- Receptors, Platelet-Derived Growth Factor/metabolism
- Umbilical Veins/cytology
- Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors*
- Vascular Endothelial Growth Factor Receptor-2/metabolism
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 21691074 Full text @ Cell Physiol. Biochem.
Citation
Cao, Z.X., Zheng, R.L., Lin, H.J., Luo, S.D., Zhou, Y., Xu, Y.Z., Zeng, X.X., Wang, Z., Zhou, L.N., Mao, Y.Q., Yang, L., Wei, Y.Q., Yu, L.T., Yang, S.Y., and Zhao, Y.L. (2011) SKLB610: A Novel Potential Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases Inhibits Angiogenesis and Tumor Growth in Vivo. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 27(5):565-574.
Abstract
Antagonizing angiogenesis-related receptor tyrosine kinase is a promising therapeutic strategy in oncology. In present study, we designed and synthesized a novel vascular endothelial growth factor receptor (VEGFR) inhibitor N-methyl-4-(4-(3-(trifluoromethyl) benzamido) phenoxy) picolinamide SKLB610 that potently suppresses human tumor angiogenesis. SKLB610 inhibited angiogenesis-related tyrosine kinase VEGFR2, fibroblast growth factor receptor 2 (FGFR2) and platelet-derived growth factor receptor (PDGFR) at rate of 97%, 65% and 55%, respectively, at concentration of 10µM in biochemical kinase assays. In vitro, SKLB610 showed more selective inhibition of VEGF-stimulated human umbilical vein endothelial cells (HUVECs) proliferation, and this proliferation inhibitory effect was associated with decreased phosphorylation of VEGFR2 and p42/44 mitogen-activated protein kinase (p42/44 MAPK). Antiangiogenic evaluation showed that SKLB610 inhibited the HUVECs capillary-tube formation on Matrigel in vitro and the sub-intestinal vein formation of zebrafish in vivo. Moreover, SKLB610 inhibited a panel of human cancer cells proliferation in a concentration-dependent manner and human non-small cell lung cancer cell line A549 and human colorectal cancer cell line HCT116 were most sensitive to SKLB610 treatment. In vivo, chronic intraperitoneally administration of SKLB610 at dose of 50mg/kg/d resulted in significant inhibition in the growth of established human A549 and HCT116 tumor xenografts in nude mice without exhibit toxicity. Histological analysis showed significant reductions in intratumoral microvessel density (CD31 staining) of 43-55% relative to controls depending on the specific tumor xenografts. In conclusion, the present study demonstrated that SKLB610 exhibited its antitumor activity as a multi-targeted inhibitor with more potent inhibition of VEGFR2 activity. Its potential to be a candidate of anticancer agent is worth being further investigated.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping