SKLB1002, A Novel Potent Inhibitor of Vascular Endothelial Growth Factor Receptor 2 Signaling, Inhibits Angiogenesis and Tumor Growth in Vivo
- Authors
- Zhang, S., Cao, Z., Tian, H., Shen, G., Ma, Y., Xie, H., Liu, Y., Zhao, C., Deng, S., Yang, Y., Zheng, R., Li, W., Zhang, N., Liu, S., Wang, W., Dai, L., Shi, S., Cheng, L., Pan, Y., Feng, S., Zhao, X., Deng, H., Yang, S.Y., and Wei, Y.Q.
- ID
- ZDB-PUB-110609-23
- Date
- 2011
- Source
- Clinical cancer research : an official journal of the American Association for Cancer Research 17(13): 4439-50 (Journal)
- Registered Authors
- Zhao, Xia
- Keywords
- none
- MeSH Terms
-
- Angiogenesis Inhibitors/chemical synthesis
- Angiogenesis Inhibitors/chemistry
- Angiogenesis Inhibitors/pharmacology*
- Angiogenesis Inhibitors/therapeutic use
- Angiogenesis Inhibitors/toxicity
- Animals
- Apoptosis/drug effects
- Cell Line
- Cell Line, Tumor
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Endothelial Cells/drug effects
- Female
- Hep G2 Cells
- Humans
- Melanoma, Experimental
- Mice
- Mice, Nude
- Neoplasm Invasiveness
- Neoplasms/drug therapy
- Neoplasms/metabolism*
- Neoplasms/pathology
- Neovascularization, Pathologic*
- Neovascularization, Physiologic/drug effects
- Quinazolines/chemical synthesis
- Quinazolines/chemistry
- Quinazolines/pharmacology*
- Quinazolines/therapeutic use
- Signal Transduction/drug effects*
- Thiadiazoles/chemical synthesis
- Thiadiazoles/chemistry
- Thiadiazoles/pharmacology*
- Thiadiazoles/therapeutic use
- Tumor Burden/drug effects
- Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors*
- Vascular Endothelial Growth Factor Receptor-2/metabolism
- Xenograft Model Antitumor Assays
- Zebrafish/embryology
- PubMed
- 21622720 Full text @ Clin. Cancer Res.
PURPOSE:
Vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors, as efficient anti-angiogenesis agents, have been applied in the cancer treatment. However, currently most of these anticancer drugs suffer some adverse effects. Discovery of novel VEGFR2 inhibitors as anticancer drug candidates is still needed.
EXPERIMENTAL DESIGN:
In this investigation, we adopted a restricted de novo design method to design VEGFR2 inhibitors. We selected the most potent compound (SKLB1002), and analyzed inhibitory effects of SKLB1002 on human umbilical vascular endothelial cells (HUVEC) in vitro. Tumor xenografts in zebrafish and athymic mice were used to examine the in vivo activity of SKLB1002.
RESULTS:
The use of the restricted de novo design method indeed led to a new potent VEGFR2 inhibitor, SKLB1002. SKLB1002 could significantly inhibit HUVEC proliferation, migration, invasion and tube formation. Western blot analysis was performed, which indicated that SKLB1002 inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including extracellular signal-regulated kinase (ERK), focal adhesion kinase (FAK) and Src. In vivo zebrafish model experiments showed that SKLB1002 remarkably blocked the formation of intersegmental vessels in zebrafish embryos. It was further found to be able to inhibit a new microvasculature in zebrafish embryos induced by inoculated tumor cells. Finally, compared with the solvent control, administration of 100 mg/kg/day SKLB1002 reached more than 60% inhibition against human tumor xenografts in athymic mice. The antiangiogenic effect was indicated by CD31 immunohistochemical staining and alginate-encapsulate tumor cell assay.
CONCLUSIONS:
Our findings suggest that SKLB1002 inhibits angiogenesis and may be a potential drug candidate in anticancer therapy.