YL529, a novel, orally available multikinase inhibitor, potently inhibits angiogenesis and tumor growth in preclinical models
- Authors
- Xu, Y.Z., Lin, H.J., Meng, N.N., Lu, W.J., Li, G., Han, Y.Y., Dai, X.Y., Xia, Y., Song, X.R., Yang, S.Y., Wei, Y.Q., Yu, L.T., and Zhao, Y.L.
- ID
- ZDB-PUB-130425-3
- Date
- 2013
- Source
- British journal of pharmacology 169(8): 1766-80 (Journal)
- Registered Authors
- Keywords
- YL529, small molecular multikinase inhibitor, anti-angiogenesis, anti-proliferation
- MeSH Terms
-
- Humans
- Cell Survival/drug effects
- Rats, Sprague-Dawley
- Male
- Lung Neoplasms/blood supply
- Lung Neoplasms/drug therapy*
- Lung Neoplasms/pathology*
- Xenograft Model Antitumor Assays
- Toxicity Tests, Acute
- Rats
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/prevention & control
- Phosphorylation/drug effects
- Female
- Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors*
- Vascular Endothelial Growth Factor Receptor-2/metabolism
- Mice
- Mice, Inbred BALB C
- Zebrafish
- Colonic Neoplasms/blood supply
- Colonic Neoplasms/drug therapy*
- Colonic Neoplasms/pathology*
- Administration, Oral
- Picolines/chemical synthesis
- Picolines/pharmacology*
- Mice, Nude
- Angiogenesis Inhibitors/chemical synthesis
- Angiogenesis Inhibitors/pharmacology*
- Neoplasm Invasiveness
- Benzenesulfonates/chemical synthesis
- Benzenesulfonates/pharmacology*
- Extracellular Signal-Regulated MAP Kinases/metabolism
- Animals
- Dogs
- Tumor Cells, Cultured/drug effects
- Tumor Cells, Cultured/pathology
- PubMed
- 23594209 Full text @ Br. J. Pharmacol.
BACKGROUND AND PURPOSE
Targeted chemotherapy using small-molecule inhibitors of angiogenesis and proliferation is a promising strategy for cancer therapy.
EXPERIMENTAL APPROACH
N-methyl-4-(4-(3-(trifluoromethyl)benzamido)phenoxy)picolinamide4- methylbenzenesulfonate (YL529) was developed via computer-aided drug design, de novo synthesis and high-throughput screening. The biochemical, pharmacodynamical, and toxicological profiles of YL529 were investigated using kinase and cell viability assay, zebrafish and mice tumor xenograft models.
KEY RESULTS
In vitro, YL529 selectively inhibited the activities of vascular endothelial growth factor receptors VEGFR2/VEGFR3 and serine/threonine kinase RAF kinase. YL529 inhibited VEGF165-induced phosphorylation of VEGFR2, as well as proliferation, migration, invasion and tube formation of human umbilical vascular endothelial cells (HUVECs). It also significantly blocked vascular formation and angiogenesis in zebrafish model. Moreover, YL529 strongly attenuated the proliferation of A549 cell line through disrupting RAF/MEK/MAPK (mitogen-activated protein kinase) pathway. Oral administration of YL529 (37.5-150 mg-1·kg-1·day-1) to nude mice bearing established tumor xenografts significantly prevented the growth (60-80%) of A549, SPC-A1, A375, OS-RC-2 and HCT116 tumors without detectable toxicity. Tumors from animals inoculated with the lung cancer cell lines SPC-A1 and A549 and the colon carcinoma cell line HCT116 revealed that YL529 treatment markedly reduced microvessel density and increased tumor cell apoptosis.
CONCLUSIONS AND IMPLICATIONS
YL529, an orally active multikinase inhibitor, shows the therapeutic potential for solid tumors, and warrants further investigation as a candidate anticancer agent.