KRN 633 286370-15-8

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Molecular Weight:

416.86 KRN 633 is an ATP-Competitive Inhibitor of VEGFR1/2/3 with IC50 of 170 nM/160 nM/125 nM, weakly inhibits PDGFR-α/β and c-Kit, does not block the phosphorylation of FGFR-1, EGFR or c-Met in cell.


Biological Activity


KRN 633, a novel quinazoline urea derivative, strongly inhibits VEGFR1,
VEGFR2 and VEGFR3 receptors with IC50 values of 170 nM, 160 nM and 125
nM respectively. It shows lower inhibitory activity towards non-RTKs,
such as PDGF receptor (PDGFRα and β, c-Kit, breast tumor kinase, and
tunica interna endothelial cell kinase tyrosine kinases (IC50 = 965,
9850, 4330, 9200, and 9900 nM, respectively). KRN 633 potently inhibits
ligand VEGF induced phosphorylation of VEGFR2 in HUVECs with an IC50 of
1.16 nM.


KRN 633 also inhibits VEGF-dependent, but not bFGF-dependent,
phosphorylation of the MAP kinases in endothelial cells, with IC50
values of 3.51 nM and 6.08 nM for ERK1 and ERK2, respectively. KRN633
has also been shown to inhibit the VEGF-driven proliferation of HUVECs
with an IC50 of 14.9 nM, but it only suppresses FGF-driven proliferation
at 3 μM weakly. KRN 633 inhibits hypoxia-induced
transcriptional activation of HIF-1α in a concentration-dependent manner
with an IC50 of 3.79 μM, through the inhibition of both Akt and ERK
phosphorylation signaling pathways.


Although not cytotoxic to various cancer cells in vitro, KRN633 exhibits
excellent antitumor activity in vivo due to its inhibitory effect on
tumor vessel formation and vascular permeability. Once-daily
administration of KRN633 at 100 mg/kg/d produces significant tumor
growth inhibition in A549, LC-6-LCK, HT29, Ls174T, LNCap and Du145 cells
while twice-daily administration of KRN633 at 100 mg/kg induces ~90%
growth inhibition of HT29 tumors. Treatment of
mid-pregnancy mice with KRN 633 (300 mg/kg, p.o.) reduces the blood
supply to fetal tissues due to diminished vascularization in both
placenta and fetal organs and consequently increases the risk of
induction of intrauterine growth restriction (IUGR).


Cell-Free Kinase Assays


Cell-free kinase assays are done to obtain IC50 values against a variety
of recombinant VEGF receptors. KRN633 is tested at concentrations
varying from 0.3 nM to 10 μM. All assays are done in quadruplicate with 1
μM ATP.


Method


Cancer cells are plated in media containig 10% FBS and antibiotics, at
densities known to permit exponential growth over the assay period. The
cells are cultured for 24 hours before adding KRN633 (0.01 to 10 μM) or
just the vehicle (0.1% DMSO in medium) and then grown for a further 96
hours. Cell viability is measured using WST-1 reagent.

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Product Categories : Protein Tyrosine Kinase > VEGFR Inhibitor