PUBLICATION
YLT192, a Novel, Orally Active Bioavailable Inhibitor of VEGFR2 Signaling with Potent Antiangiogenic Activity and Antitumor Efficacy in Preclinical Models
- Authors
- Xia, Y., Song, X., Li, D., Ye, T., Xu, Y., Lin, H., Meng, N., Li, G., Deng, S., Zhang, S., Liu, L., Zhu, Y., Zeng, J., Lei, Q., Pan, Y., Wei, Y., Zhao, Y., Yu, L.
- ID
- ZDB-PUB-140813-8
- Date
- 2014
- Source
- Scientific Reports 4: 6031 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Angiogenesis Inhibitors/chemistry
- Angiogenesis Inhibitors/pharmacology*
- Angiogenesis Inhibitors/therapeutic use
- Animals
- Antineoplastic Agents/pharmacology
- Benzamides/chemistry
- Benzamides/pharmacology*
- Benzamides/therapeutic use
- Binding Sites
- Cell Line, Tumor
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/metabolism
- Female
- HCT116 Cells
- Human Umbilical Vein Endothelial Cells
- Humans
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Neoplasms/drug therapy
- Neoplasms/pathology
- Neovascularization, Physiologic/drug effects
- Picolinic Acids/chemistry
- Picolinic Acids/pharmacology*
- Picolinic Acids/therapeutic use
- Protein Structure, Tertiary
- Rats
- Rats, Wistar
- Signal Transduction/drug effects
- Vascular Endothelial Growth Factor A/pharmacology
- Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors*
- Vascular Endothelial Growth Factor Receptor-2/metabolism
- Zebrafish/growth & development
- PubMed
- 25112436 Full text @ Sci. Rep.
Citation
Xia, Y., Song, X., Li, D., Ye, T., Xu, Y., Lin, H., Meng, N., Li, G., Deng, S., Zhang, S., Liu, L., Zhu, Y., Zeng, J., Lei, Q., Pan, Y., Wei, Y., Zhao, Y., Yu, L. (2014) YLT192, a Novel, Orally Active Bioavailable Inhibitor of VEGFR2 Signaling with Potent Antiangiogenic Activity and Antitumor Efficacy in Preclinical Models. Scientific Reports. 4:6031.
Abstract
Antagonizing vascular endothelial growth factor receptor 2 (VEGFR2) to block angiogenesis has been applied toward cancer therapy for its role in promoting cancer growth and metastasis. However, most these clinical anticancer drugs have unexpected side effects. Development of novel VEGFR2 inhibitors with less toxicity remains an urgent need. In this study, we describe a novel, well-tolerated, and orally active VEGFR2 inhibitor, YLT192, which inhibits tumor angiogenesis and growth. YLT192 significantly inhibited kinase activity of VEGFR2 and suppressed proliferation, migration, invasion, and tube formation of human umbilical vascular endothelial cells (HUVEC) in vitro. In addition, it inhibited VEGF-induced phosphorylation of VEGFR2 and its downstream signaling regulator in HUVEC. Zebrafish embryonic models and alginate-encapsulated tumor cell assays indicated YLT192 also inhibited angiogenesis in vivo. Moreover, YLT192 could directly inhibit proliferation and induce apoptosis of cancer cells in vitro and in vivo. Oral administration of YLT192 at a dose of 100 mg/kg/day could markedly inhibited human tumor xenograft growth without causing obvious toxicities. It decreased microvessel densities (MVD) in tumor sections. It also shows good safety profiles in the studies with mice and rats. Taken together, these preclinical evaluations suggest that YLT192 inhibits angiogenesis and may be a promising anticancer drug candidate.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping