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Purity: ≥98%
Ki8751 (Ki-8751), a quinolyloxyphenyl-urea analog, is a novel, cell-permeable and selective inhibitor of VEGFR2 (Flk-1) with potential anticancer activity. With an IC50 of 0.9 nM, it inhibits VEGFR2 (Flk-1) and exhibits over 40-fold selectivity for VEGFR2 in comparison to c-Kit (IC50 = 40 nM), PDGFRα (IC50 = 67 nM), and FGFR-2 (IC50 = 170 nM). minimal/none effects on InsR, HGFR, and EGFR. With human tumor xenografts of GL07, St-4, LC6, DLD-1, and A375 cells, it shows strong in vivo antitumor efficacy and outstanding anti-proliferative activity in naked mice and rats.
| Targets |
VEGFR2 (IC50 = 0.9 nM); c-Kit (IC50 = 40 nM); PDGFRα (IC50 = 67 nM)
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| ln Vitro |
Ki8751 inhibits the phosphorylation of VEGFR-2 at an IC50 value of 0.90 nM. It also blocks the PDGFR family members, including c-Kit and PDGFRR, at 40 nM and 67 nM, respectively. Even at 10000 nM, however, Ki8751 exhibits no inhibitory activity against other kinases, including EGFR, HGFR, InsulinR, and others." At the nanomolar level, VEGF-stimulated human umbilical vein endothelial cells (HUVECs) are inhibited by Ki8751[1].
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| ln Vivo |
Ki8751 exhibits noteworthy antitumor activity in nude mice against five human tumor xenografts, including GL07 (glioma), St-4 (stomach carcinoma), LC6 (lung carcinoma), DLD-1 (colon carcinoma), and A375 (melanoma). Additionally, in nude rats, the LC-6 xenograft completely inhibits tumor growth after oral administration once daily for 14 days at a dose of 5 mg/kg without causing any loss of body weight[1].
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| Enzyme Assay |
NIH3T3 cells created through human KDR transfection. 1.5 × 104 cells per well are cultured in a 96-well plate coated with collagen type I. Next, a DMEM medium containing 0.1% FCS is added to replace the original medium. After being added to each well, diluted Ki8751 in DMSO is cultured. The cells are stimulated at 37 °C with rhVEGF added at a final concentration of 100 ng/mL. After washing the cells with PBS (pH 7.4), a cell extract is made by adding 50 μL of a solubilization buffer (20 mM HEPES (pH 7.4), 150 mM NaCl, 0.2% Triton X-100, 10% glycerol, 5 mM Na3VO4, 5 mM disodium ethylenediamine tetraacetate, and 2 mM Na4P2O7). ELISA requires the addition of 5 μg/mL of antiphosphotyrosine antibody (PY20) to 50 μL of pH 7.4 PBS to a microplate. Add 300 μL of a blocking solution to the plate after it has been cleaned. Once on the plate, the cell extract is moved. The addition of an anti-VEGFR2 antibody and an anti-rabbit Ig antibody labeled with peroxidase is performed. The absorbance at 450 nm is then measured using a microplate reader after the addition of a chromophoric substrate for peroxidase. The calculation of the VEGFR2 phosphorylation activity for every well involves making the assumption that the absorbance increases to 100% when VEGF is added and to 0% when the test sample is not added. For every instance, the percentage of VEGFR2 phosphorylation that is inhibited is calculated, and the IC50 value is determined.
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| Cell Assay |
HUVECs are plated in type I collagen-precoated 96-well plates at a density of 4000 cells/200 μL/well in order to assess the inhibition of VEGF-Stimulated HUVEC proliferation by Ki8751. Following a 24-hour period, the cells are stimulated with 20 ng/mL rhVEGF after being incubated with Ki8751 for an hour. The cultures are first incubated for 72 hours at 37 °C, followed by a 14-hour re-incubation after receiving a pulse of 1 Ci/well [3H]thymidine. A beta counter is used to measure the incorporation of tritium in cells.
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| Animal Protocol |
Mice: Human tumor xenografts in nude mice are used to test the effects of Ki8751 on tumor growth against a variety of tumors, including human melanoma (A375), human stomach carcinoma (St-4), human lung carcinoma (LC-6), and human colon carcinoma (DLD-1). For nine days in a row, mice in the experimental groups receive 5 mg/kg of Ki8751 orally once daily, while control animals receive the vehicle. Every two weeks, tumor volumes are checked[1].
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| References |
| Molecular Formula |
C24H18F3N3O4
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| Molecular Weight |
469.41
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| Exact Mass |
469.12
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| Elemental Analysis |
C, 61.41; H, 3.87; F, 12.14; N, 8.95; O, 13.63
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| CAS # |
228559-41-9
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| Related CAS # |
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| Appearance |
White to off-white solid powder
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| SMILES |
COC1=CC2=C(C=CN=C2C=C1OC)OC3=CC(=C(C=C3)NC(=O)NC4=C(C=C(C=C4)F)F)F
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| InChi Key |
LFKQSJNCVRGFCC-UHFFFAOYSA-N
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| InChi Code |
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)
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| Chemical Name |
1-(2,4-difluorophenyl)-3-[4-(6,7-dimethoxyquinolin-4-yl)oxy-2-fluorophenyl]urea
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| Synonyms |
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| HS Tariff Code |
2934.99.03.00
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (5.33 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (5.33 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.33 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 4% DMSO+corn oil: 2.5mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1303 mL | 10.6517 mL | 21.3033 mL | |
| 5 mM | 0.4261 mL | 2.1303 mL | 4.2607 mL | |
| 10 mM | 0.2130 mL | 1.0652 mL | 2.1303 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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