WP1066 857064-38-1

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Molecular Weight:

356.22 WP1066 is a novel inhibitor of JAK2 and STAT3 with IC50 of 2.30 μM and 2.43 μM in HEL cells; shows activity to JAK2, STAT3, STAT5, and ERK1/2 not JAK1 and JAK3. Phase 1.


Biological Activity


WP1066 markedly inhibits the growth of HEL cells carrying the JAK2 V617F
mutant isoform in a dose-dependent manner with IC20, IC50 and IC80 of
0.8, 2.3 and 3.8 μM. WP1066 at concentrations of 0.5, 1.0, 2.0, 3.0, or
4.0 μM inhibits the phosphorylation of JAK2, STAT3, STAT5, and ERK1/2
without affecting the phosphorylation of JAK1 and JAK3 in erythroid
leukemia HEL cells that express the JAK2 V617F isoform.


WP1066 at concentrations ranging from 0.5 to 3.0 μM inhibits the
proliferation of AML colony-forming cells obtained from patients and
that of the AML cell lines OCIM2 and K562 in a dose-dependent manner.
WP1066 at concentrations of 0.5, 1.0, 2.0, 3.0, or 4.0 μM
dose-dependently decreases JAK2 and pJAK2 protein levels as well as
downstream phosphorylation levels of STAT3, STAT5, and AKT in OCIM2 and
K562 cells. WP1066 at concentrations of 2 μM inhibits OCIM2 cell
multiplication by inducing accumulation of cells at the G0-G1 phase of
the Cell Cycle.


WP1066 at concentrations of 1, 2, or 3 μM induces
Apoptosis in both OCIM2 and K562 cells in a dose-dependent fashion by
activating procaspase-3 and cleaving PARP. WP1066 at
concentrations of 5 μM prevents the phosphorylation of STAT3, and at
concentrations of 2.5μM WP1066 significantly inhibits cell survival and
proliferation in Caki-1 and 786-O renal cancer cells. WP1066 at
concentrations of 5 μM suppresses HIF1α and HIF2α expression and VEGF
production in Caki-1 and 786-O renal cancer cells.


WP1066 orally administrated at dose of 40 mg/kg once daily for 19 days
significantly inhibits the tumours growth in Caki-1 xenograft mice, with
decreased immunostaining of phosphorylated STAT3 and reduced length of
CD34-positive vessels.






Method


The
3,
[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H-tetrazolium
(MTT) assay is done using an MTT-based cell proliferation/cytotoxicity
assay system. Briefly, fresh low-density peripheral blood cells and
various cell lines at the logarithmic phase of their growth are washed
twice in RPMI 1640 containing 10% FCS and counted in a hemocytometer.


Cell viability is assessed by the trypan blue (0.1%) staining method.
Equal numbers of viable cells (5 × 104 per well) are
incubated in a total volume of 100 μL of RPMI 1640 supplemented with 10%
FCS alone or with WP1066 at increasing concentrations; the incubations
are continued for up to 72 h in 96-well flat-bottomed plates at 37 °C in
a humidified 5% CO2 atmosphere. Experiments for each
condition are done in triplicate.


After incubation, 20 μL of CellTiter96
One Solution Reagent are added to each well. The plates are then
incubated for an additional 60 min at 37 °C in a humidified 5% CO2 atmosphere. Immediately after incubation, absorbance is read using a 96-well plate reader at a wavelength of 490 nm.

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Product Categories : Epigenetics > JAK Inhibitor