Ki8751 228559-41-9

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Molecular Weight:

469.41 Ki8751 is a potent and selective inhibitor of VEGFR2 with IC50 of 0.9 nM, >40-fold selective for VEGFR2 than c-Kit, PDGFRα and FGFR-2, little activity to EGFR, HGFR and InsR.


Biological Activity


Ki8751 potently and selectively inhibits VEGFR2 with IC50 of 0.9 nM.
Ki8751 also inhibits PDGFRα, c-Kit, and FGFR-2, with much higher IC50
values (40 nM–170 nM). Except for these several kinases, Ki8751 doesn't
disturb other kinases, including HGFR, EGFR, and InsulinR, even at 10
μM. In human umbilical vein endothelial cells (HUVECs),
Ki8751 (1 nM–100 nM) effectively decreases VEGF-stimulated cell
proliferation and vasculature permeability. In metastatic
colorectal cancer (CRC) cells MIP, RKO, SW620, and SW480, but not in
HCT116, Ki8751 (10 nM) increases cellular senescence.


In
nude mice bearing human tumor xenografts of GL07, St-4, LC6, DLD-1, and
A375 cells, Ki8751 (20 mg/kg) inhibits tumor growth. In nude rat
xenograft models of LC-6 cells, Ki8751 (5 mg/kg) completely inhibits
tumor growth without affecting body weight.






Cellular Kinase Assays


NIH3T3 cells prepared by transfection of human KDR. The cells are
cultured in a collagen type I coated 96-well plate in an amount of 1.5 ×
104 per well. The medium is then replaced by a DMEM medium
containing 0.1% FCS. Ki8751 diluted in DMSO is added to each well and
cultured. rhVEGF is added to a final concentration of 100 ng/mL, and the
stimulation of cells is carried out at 37 °C.


The cells are washed with
PBS (pH 7.4), 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)
is then added and a cell extract is prepared. Separately, PBS (50 μL,
pH 7.4) containing 5 μg/mL of antiphosphotyrosine antibody (PY20) is
added to a microplate for ELISA. After washing of the plate, 300 μL of a
blocking solution is added. The cell extract is transferred to the
plate.


An anti-VEGFR2 antibody and a peroxidase-labeled anti-rabbit Ig
antibody are added. Next, a chromophoric substrate for peroxidase is
added, and the absorbance at 450 nm is measured with microplate reader.
The VEGFR2 phosphorylation activity for each well is determined by
presuming the absorbance with the addition of VEGF and without the
addition of the test sample to be 100% VEGFR2 phosphorylation activity
and VEGF to be 0% VEGFR2 phosphorylation activity. The concentration of
the inhibition (%) of VEGFR2 Phosphorylation is determined for each
case, and IC50 value is calculated.

Method

To evaluate the inhibition of VEGF-Stimulated HUVEC proliferation by
Ki8751, HUVECs are plated at a density of 4000 cells/200 μL/well in a
type I collagen pre-coated 96-well plates. After 24 hours, the cells are
incubated for 1 hour with Ki8751 and then stimulated with 20 ng/mL
rhVEGF. The cultures are incubated at 37 °C for 72 hours, then pulsed
with 1 μCi/well [3H]thymidine and re-incubated for 14 hours. Cells are assayed for the incorporation of tritium using a beta counter.

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Product Categories : Protein Tyrosine Kinase > VEGFR Inhibitor