Ki8751VEGFR-2 inhibitor,potent and selective CAS# 228559-41-9 |
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Quality Control & MSDS
Number of papers citing our products
Chemical structure
3D structure
Cas No. | 228559-41-9 | SDF | Download SDF |
PubChem ID | 11317348 | Appearance | Powder |
Formula | C24H18F3N3O4 | M.Wt | 469.41 |
Type of Compound | N/A | Storage | Desiccate at -20°C |
Solubility | DMSO : ≥ 92 mg/mL (195.99 mM) H2O : < 0.1 mg/mL (insoluble) *"≥" means soluble, but saturation unknown. | ||
Chemical Name | 1-(2,4-difluorophenyl)-3-[4-(6,7-dimethoxyquinolin-4-yl)oxy-2-fluorophenyl]urea | ||
SMILES | COC1=CC2=C(C=CN=C2C=C1OC)OC3=CC(=C(C=C3)NC(=O)NC4=C(C=C(C=C4)F)F)F | ||
Standard InChIKey | LFKQSJNCVRGFCC-UHFFFAOYSA-N | ||
Standard InChI | InChI=1S/C24H18F3N3O4/c1-32-22-11-15-20(12-23(22)33-2)28-8-7-21(15)34-14-4-6-19(17(27)10-14)30-24(31)29-18-5-3-13(25)9-16(18)26/h3-12H,1-2H3,(H2,29,30,31) | ||
General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. |
Description | Potent, selective inhibitor of VEGFR-2 tyrosine kinase (IC50 = 0.9 nM). Displays some inhibitory activity towards c-Kit, PDGFRα and FGFR-2 (IC50 values range from 40 to 170 nM) but is highly selective over other receptor tyrosine kinases (IC50 > 10000 nM for FGFR-2, EGFR and HGFR). Inhibits VEGF-stimulated proliferation of human umbilical vein endothelial cells (HUVEC) and inhibits tumor growth in vivo; antiangiogenic. |
Ki8751 Dilution Calculator
Ki8751 Molarity Calculator
1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
1 mM | 2.1303 mL | 10.6517 mL | 21.3033 mL | 42.6067 mL | 53.2583 mL |
5 mM | 0.4261 mL | 2.1303 mL | 4.2607 mL | 8.5213 mL | 10.6517 mL |
10 mM | 0.213 mL | 1.0652 mL | 2.1303 mL | 4.2607 mL | 5.3258 mL |
50 mM | 0.0426 mL | 0.213 mL | 0.4261 mL | 0.8521 mL | 1.0652 mL |
100 mM | 0.0213 mL | 0.1065 mL | 0.213 mL | 0.4261 mL | 0.5326 mL |
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. |
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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].
References:
[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.
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Vascular Endothelial Growth Factor-A Increases the Aqueous Humor Outflow Facility.[Pubmed:27584577]
PLoS One. 2016 Sep 1;11(9):e0161332.
PURPOSE: Anti-vascular endothelial growth factor (VEGF) antibody therapy is an effective treatment for ocular angiogenesis. Although the intraocular pressure of some patients increases after anti-VEGF therapy, the effects of VEGF-A on the aqueous humor outflow pathway remain unknown. This study investigated the effects of VEGF-A on the aqueous humor outflow pathway. METHODS: We used human recombinant VEGF121 and VEGF165. Trabecular meshwork (TM) and Schlemm's canal endothelial (SCE) cells were isolated from the eyes of cynomolgus monkeys. Expression of mRNA coding four VEGF receptors, VEGFR1 (FLT1), VEGFR2 (KDR), neuropilin-1, and neuropilin-2, was examined by RT-PCR. To evaluate the permeability of cell monolayers, we measured transendothelial electrical resistance (TEER). The outflow facility was measured in perfused porcine anterior segment organ cultures treated with 30 ng/mL VEGF121 for 48 h. RESULTS: Four VEGF-A-related receptor mRNAs were expressed in TM and SCE cells. The TEER of TM cells was not significantly affected by VEGF121 or VEGF165 treatment. In contrast, the TEER of SCE cells was significantly lower 48 h after treatment with 30 ng/mL VEGF121 to 69.4 +/- 12.2% of baseline (n = 10), which was a significant difference compared with the control (P = 0.0001). VEGF165 (30 ng/mL) decreased the TEER of SCE cells at 48 h after treatment to 72.3 +/- 14.1% compared with the baseline (n = 10), which was not a significant difference compared with the control (P = 0.0935). Ki8751, a selective VEGFR2 inhibitor, completely suppressed the effect of VEGF121 on SCE cell permeability, although ZM306416, a selective VEGFR1 inhibitor, did not affect the VEGF121-induced decrease in TEER. Perfusion with 30 ng/mL of VEGF121 for 48 h significantly increased the outflow facility compared with the control (47.8 +/- 28.5%, n = 5, P = 0.013). CONCLUSIONS: These results suggest that VEGF-A may regulate the conventional aqueous outflow of SCE cells through VEGFR2.
Branching of lung epithelium in vitro occurs in the absence of endothelial cells.[Pubmed:25581492]
Dev Dyn. 2015 Apr;244(4):553-63.
BACKGROUND: Early lung morphogenesis is driven by tissue interactions. Signals from the lung mesenchyme drive epithelial morphogenesis, but which individual mesenchymal cell types are influencing early epithelial branching and differentiation remains unclear. It has been shown that endothelial cells are involved in epithelial repair and regeneration in the adult lung, and they may also play a role in driving early lung epithelial branching. These data, in combination with evidence that endothelial cells influence early morphogenetic events in the liver and pancreas, led us to hypothesize that endothelial cells are necessary for early lung epithelial branching. RESULTS: We blocked vascular endothelial growth factor (VEGF) signaling in embryonic day (E) 12.5 lung explants with three different VEGF receptor inhibitors (SU5416, Ki8751, and KRN633) and found that in all cases the epithelium was able to branch despite the loss of endothelial cells. Furthermore, we found that distal lung mesenchyme depleted of endothelial cells retained its ability to induce terminal branching when recombined with isolated distal lung epithelium (LgE). Additionally, isolated E12.5 primary mouse lung endothelial cells, or human lung microvascular endothelial cells (HMVEC-L), were not able to induce branching when recombined with LgE. CONCLUSIONS: Our observations support the conclusion that endothelial cells are not required for early lung branching.
VEGF as a Paracrine Regulator of Conventional Outflow Facility.[Pubmed:28358962]
Invest Ophthalmol Vis Sci. 2017 Mar 1;58(3):1899-1908.
Purpose: Vascular endothelial growth factor (VEGF) regulates microvascular endothelial permeability, and the permeability of Schlemm's canal (SC) endothelium influences conventional aqueous humor outflow. We hypothesize that VEGF signaling regulates outflow facility. Methods: We measured outflow facility (C) in enucleated mouse eyes perfused with VEGF-A164a, VEGF-A165b, VEGF-D, or inhibitors to VEGF receptor 2 (VEGFR-2). We monitored VEGF-A secretion from human trabecular meshwork (TM) cells by ELISA after 24 hours of static culture or cyclic stretch. We used immunofluorescence microscopy to localize VEGF-A protein within the TM of mice. Results: VEGF-A164a increased C in enucleated mouse eyes. Cyclic stretch increased VEGF-A secretion by human TM cells, which corresponded to VEGF-A localization in the TM of mice. Blockade of VEGFR-2 decreased C, using either of the inhibitors SU5416 or Ki8751 or the inactive splice variant VEGF-A165b. VEGF-D increased C, which could be blocked by Ki8751. Conclusions: VEGF is a paracrine regulator of conventional outflow facility that is secreted by TM cells in response to mechanical stress. VEGF affects facility via VEGFR-2 likely at the level of SC endothelium. Disruption of VEGF signaling in the TM may explain why anti-VEGF therapy is associated with decreased outflow facility and sustained ocular hypertension.
Platelet releasate promotes breast cancer growth and angiogenesis via VEGF-integrin cooperative signalling.[Pubmed:28697175]
Br J Cancer. 2017 Aug 22;117(5):695-703.
BACKGROUND: Selective platelet release of pro- or anti-angiogenic factors distinctly regulated angiogenesis. We hypothesised that selective release of platelet angiogenic factors could differently regulate tumour growth. METHODS: Breast cancer cell proliferation, cancer cell-induced endothelial tube formation in vitro, and tumour growth in vivo were studied in the presence of protease-activated receptor 1-stimulated platelet releasate (PAR1-PR; rich in pro-angiogenic factors) or PAR4-PR (rich in anti-angiogenic factors). RESULTS: The PAR1-PR and PAR4-PR supplementation (10%) similarly enhanced cell proliferation of MCF-7 and MDA-MB-231 breast cancer cells. The cancer cells triggered capillary-like tube formation of endothelial cells that was further enhanced by pro-angiogenic factor-rich PAR1-PR. The VEGF, but not SDF-1alpha, receptor blockade abolished PAR1-PR/PAR4-PR-enhanced cancer cell proliferation. Integrin blockade by RGDS had identical effects as VEGF inhibition. The Src and ERK inhibition diminished, whereas PI3K and PKC blockade abolished platelet releasate-enhanced cancer cell proliferation. Using a model of subcutaneous implantation of MDA-MB-231 cells in nude mice, PAR1-PR enhanced tumour growth more markedly than PAR4-PR, and seemed to achieve the exaggeration by promoting more profound tumour angiogenesis. CONCLUSIONS: Platelet releasate increases breast cancer cell proliferation through VEGF-integrin cooperative signalling. Pro-angiogenic factor-rich platelet releasate enhances cancer cell-induced angiogenesis more markedly, and thus exaggerates tumour growth in vivo.
Vascular endothelial growth factor-D mediates fibrogenic response in myofibroblasts.[Pubmed:26724950]
Mol Cell Biochem. 2016 Feb;413(1-2):127-35.
Vascular endothelial growth factor (VEGF)-D is a crucial mediator of angiogenesis. Following myocardial infarction (MI), cardiac VEGF-D and VEGF receptor (VEGFR)-3 are significantly upregulated. In addition to endothelial cells, myofibroblasts at the site of MI highly express VEGFR-3, implicating the involvement of VEGF-D in cardiac fibrogenesis that promotes repair and remodeling. The aim of the current study was to further explore the critical role of VEGF-D in fibrogenic response in myofibroblasts. Myofibroblast proliferation, migration, collagen synthesis, and degradation were investigated in cultured cardiac myofibroblasts subjected to VEGF-D with/without VEGFR antagonist or ERK inhibitor. Vehicle-treated cells served as controls. Myofibroblast proliferation and migration were detected by BrdU assay and Boyden Chamber method, respectively. Expression of type I collagen, metalloproteinase (MMP)-2/-9, tissue inhibitor of MMP (TIMP)-1/-2, and ERK phosphorylation were evaluated by Western blot analyses. Our results revealed that compared to controls, (1) VEGF-D significantly increased myofibroblast proliferation and migration; (2) VEGF-D significantly upregulated type I collagen synthesis in a dose- and time-dependent manner; (3) VEGFR antagonist abolished VEGF-D-induced myofibroblast proliferation and type I collagen release; (4) VEGF-D stimulated MMP-2/-9 and TIMP-1/-2 synthesis; (5) VEGF-D activated ERK phosphorylation; and (6) ERK inhibitor abolished VEGF-D-induced myofibroblast proliferation and type I collagen synthesis. Our in vitro studies have demonstrated that VEGF-D serves as a crucial profibrogenic mediator by stimulating myofibroblast growth, migration and collagen synthesis. Further studies are underway to determine the role of VEGF-D in fibrous tissue formation during cardiac repair following MI.
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.[Pubmed:15743179]
J Med Chem. 2005 Mar 10;48(5):1359-66.
N-Phenyl-N'-{4-(4-quinolyloxy)phenyl}ureas were found to be a novel class of potent inhibitors for the vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase through synthetic modifications of a lead compound and structure-activity relationship studies. A representative compound 6ab, termed Ki8751, inhibited VEGFR-2 phosphorylation at an IC(50) value of 0.90 nM, and also inhibited the PDGFR family members such as PDGFRalpha and c-Kit at 67 nM and 40 nM, respectively. However, 6ab did not have any inhibitory activity against other kinases such as EGFR, HGFR, InsulinR and others even at 10000 nM. 6ab suppressed the growth of the VEGF-stimulated human umbilical vein endothelial cell (HUVEC) on a nanomolar level. 6ab showed significant antitumor activity against five human tumor xenografts such as GL07 (glioma), St-4 (stomach carcinoma), LC6 (lung carcinoma), DLD-1 (colon carcinoma) and A375 (melanoma) in nude mice and also showed complete tumor growth inhibition with the LC-6 xenograft in nude rats following oral administration once a day for 14 days at 5 mg/kg without any body weight loss.