ENMD-2076 934353-76-1

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Molecular Weight:

375.47 ENMD-2076 has selective activity against Aurora A and Flt3 with IC50 of 14 nM and 1.86 nM, 25-fold selective for Aurora A than over Aurora B and less potent to VEGFR2/KDR and VEGFR3, FGFR1 and FGFR2 and PDGFRα. Phase 2.


Biological Activity


ENMD-2076 indicates activity against multiple kinases involved in
Angiogenesis, including FLT3, RET, FLT4/VEGFR3, SRC, NTRK1, CSF1R/FMS,
LCK, VEGFR2/KDR, FGFR1/2, and PDGFRα with IC50 from 1.86-120 nM.
ENMD-2076 inhibits the growth of a wide range of human solid tumor and
hematopoietic cancer cell lines with IC50 from 0.025 to 0.7 μM, which
induces Apoptosis and G2/M phase arrest.


ENMD-2076 induces regression or
complete inhibition of tumor growth in tumor xenograft models derived
from breast, colon, melanoma, leukemia, and multiple myeloma cell lines. ENMD-2076 is the L (+) tartrate salt of ENMD-981693.
ENMD-2076 shows significant cytotoxicity against myeloma cell lines
(IM9, ARH-77, U266, RPMI 8226, MM.1S, MM.1R, NCI-H929) and primary cells
with IC50 from 2.99 to 7.06 μM, which induces apoptosis.


ENMD-2076
indicates low cytotoxicity to haematopoietic progenitors. ENMD-2076
inhibits the phosphoinositide 3-kinase/Akt pathway and downregulates
survivin and X-linked inhibitor of apoptosis. ENMD-2076 also inhibits
aurora A and B kinases, and induces G2/M Cell Cycle arrest.


ENMD-2076 has sustained inhibitory effects on the activation of Flt3 as
well as VEGFR2/KDR and FGFR1/2 in HT29 xenograft model. ENMD-2076 could
prevent the formation of new blood vessels and regress formed vessels in
MDA-MB-231 xenograft model.


Oral treatment with
ENMD-2076 (50, 100, 200 mg/kg per day) inhibits the tumour growth in
H929 human plasmacytoma xenografts, with significant reduction in
phospho-Histone 3 (pH3), Ki-67, and angiogenesis, and also a significant
increase in cleaved caspase-3.






Kinase assays


Recombinant Aurora A and B kinase enzymes and appropriate PanVera
Z'-Lyte kinase assay kits are purchased. Assays are carried out in
kinase assay buffer (50 mM of HEPES, pH 7.5, 10 mM of MgCl2, 5
mM of EGTA, 0.05% Brij-35) supplemented with 2 mM of DTT. Activities
are determined at an ATP concentration equivalent to the apparent Km for
each enzyme, and an enzyme concentration that results in approximately
30% phosphorylation of the peptide substrate after 1 hour.


Dose–response
curves of relative enzyme activity versus ENMD-2076 concentration are
plotted with Grafit and used to calculate IC50 values. Potency of
ENMD-2076 free base against a select panel of 100 kinase enzymes is
determined using the SelectScreen kinase profiling service.


ATP
concentrations are at the apparent Km for each enzyme or 100 μM if the
apparent Km could not be reached. Percent inhibition is determined at an
ENMD-2076 free base concentration of 1 μM; for kinases where
significant inhibition is noted, IC50 values are determined by
generating full 10-point dose–response curves.

Method

The antiproliferative effect of ENMD-2076 on adherent tumor cell lines
is measured by plating 500 cells per well in a 96-well plate and
incubating with ENMD-2076 for 96 hours. Cellular proliferation is
measured using the sulforhodamine B assay. The leukemia-derived,
nonadherent cell lines are assayed by plating 5 × 103 cells
per well in a 96-well plate. The cells are incubated with ENMD-2076 for
48 hours and then survival is assayed using the Alamar Blue reagent.


To
measure the effect of ENMD-2076 on VEGF- and fibroblast growth factor
(FGF)-induced proliferation of human umbilical vein endothelial cell
(HUVEC), cells are serum starved for 6 hours, then treated with
ENMD-2076 free base, and stimulated with 5 ng/mL bFGF or 25 ng/mL VEGF
(R and D Systems) for 72 hours. Cell proliferation is measured using
WST-

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Product Categories : Protein Tyrosine Kinase > FLT3 Inhibitor