A potent, orally available VEGFR2 inhibitor
Ki8751 is a selective and potent inhibitor of VEGFR2 with IC50 value of 0.9 nM [1].
VEGF receptors are receptors for vascular endothelial growth factor (VEGF) and regulate angiogenesis [2].
In cell-based assays, Ki8751 inhibited VEGFR2 with IC50 value of 0.9 nM. And it also inhibited c-Kit (IC50 40 nM), PDGFRα(IC50 67 nM), and FGFR-2 (IC50 170 nM) [1]. Treatment human umbilical vein endothelial cells (HUVECs) with Ki8751 (0.01, 0.1, 1, 10, 100 nM) caused inhibition of HUVEC growth in a dose-dependent way and completely suppressed it at 1 nM [1]. In metastatic colorectal cancer (CRC) cells of MIP, RKO, SW620, and SW480, Ki8751 (10 nM) induced cellular senescence [2].
In nude mice using xenografts of human glioma GL07, human stomach carcinoma St-4, human lung carcinoma LC-6, human colon carcinoma DLD-1 and human melanoma A375 cells, Ki8751 inhibited tumor growth. In nude rats using LC-6 human tumor xenografts, Ki8751 inhibited tumor growth, but then tumor regrowth was observed [1].
参考文献:
[1]. Kubo K, Shimizu T, Ohyama S, et al. Novel potent orally active selective VEGFR-2 tyrosine kinase inhibitors: synthesis, structure-activity relationships, and antitumor activities of N-phenyl-N'-{4-(4-quinolyloxy)phenyl}ureas. J Med Chem, 2005, 48(5): 1359-1366.
[2]. Hasan MR, Ho SH, Owen DA, et al. Inhibition of VEGF induces cellular senescence in colorectal cancer cells. Int J Cancer, 2011, 129(9): 2115–2123.
Kinase experiment: | VEGFR-2 kinase assay is described below; GST-fusion proteins of KDR (Flk-1: cytoplasmic domain) are produced in the baculo-virus expression system. GST-KDR is premixed with a serial dilution of Ki8751 in the kinase buffer. The kinase reaction is initiated by the addition of 2 μM ATP in a solution of MnCl2. After 20 min incubation at room temperature, the reaction is stopped with an addition of EDTA. Phosphorylation levels of GST-KDR are detected by immunoblotting with anti-phosphotyrosine monoclonal antibodies (PY20) and detected by ECL fluorography[1]. |
Cell experiment: | HUVECs are placed at a density of 4000 cells/200 μL/well on collagene type I precoated 96-well plates in M199 medium with 5% fetal bovine serum (FBS). After 24 h, the cells are incubated for 1 h in the presence or absence of Ki8751; then the cells are stimulated by rhVEGF (20 ng/mL). The cultures are incubated at 37 °C for 72 h, then pulsed with 1 μCi/well [3H]thymidine and reincubated for 14 h. Cells are assayed for the incorporation of tritium using a beta counter[1]. |
Animal experiment: | Mice: The effects of Ki8751 on tumor growth is tested against various tumors, human stomach carcinoma (St-4), human lung carcinoma (LC-6), human colon carcinoma (DLD-1) and human melanoma (A375), using human tumor xenografts in nude mice. Ki8751 is administered orally to mice in the experimental groups once a day for 9 consecutive days at 5 mg/kg, and the vehicle is administered to control animals. Tumor volumes are monitored twice weekly[1]. |
参考文献: [1]. Kubo K, et al. Novel potent orally active selective VEGFR-2 tyrosine kinase inhibitors: synthesis, structure-activity relationships, and antitumor activities of N-phenyl-N'-{4-(4-quinolyloxy)phenyl}ureas. J Med Chem, 2005, 48(5), 1359-1366. | |
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