ZM 447439 331771-20-1

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Molecular Weight:

513.59 ZM 447439 is a selective and ATP-Competitive Inhibitor for Aurora A and Aurora B with IC50 of 110 nM and 130 nM, respectively. It is more than 8-fold selective for Aurora A/B than MEK1, Src, Lck and has little effect against CDK1/2/4, Plk1, Chk1, etc.


Biological Activity


In vitro, ZM-447439 selectively inhibits recombinant human Aurora A and B
with IC50 values of 110 and 130 nM, respectively, while other protein
kinases of diverse structural types including the mitotic kinases CDK1
and PLK1 are inhibited with IC50 values >10 μM. Aurora
kinase inhibitor, ZM-447439 time- and dose-dependently inhibits the
growth of all three cell lines with IC50 values of 3 μM (BON), 0.9 μM
(QGP-1) and 3 μM (MIP-101) after 72 hours of continuous exposure.


In
addition, ZM-447439 potently induces cell Apoptosis by promoting DNA
fragmentation and caspase 3 and 7 activation, and arrests GEP-NET cells
in the G0 /G1and G2/M phase of the Cell Cycle. In mouse embryo, inhibition of Aurora kinase activity by ZM-447439
results in abnormalities during mitosis by regulating the
phosphorylation of histone H3 serine 10 (H3S10Ph) from G2 to metaphase
with different perturbations in each embryonic cycle. A
recent study shows that ZM-447439 exhibits growth inhibitory and
proapoptotic effect on cervical cancer SiHa cells, and enhances the
chemosensitivity to cisplatin.






In vitro kinase assays


Recombinant Aurora A and B are expressed as NH2-terminal His6-tagged
fusion Proteins using a baculovirus expression system. Aurora A is
purified by affinity chromatography using Ni-NTA agarose, and Aurora B
is purified by ion exchange chromatography using CM Sepharose Fast Flow.
1 ng purified recombinant enzyme is added to a reaction cocktail
containing 25 mM Tris-HCl, pH 7.5, 12.5 mM KCl, 2.5 mM NaF, 0.6 mM DTT,
6.25 mM MnCl2, 10 μM peptide substrate, 10 μM for Aurora A or 5 μM ATP for Aurora B, and 0.2 μCi γ-[33P]ATP
(specific activity ≥2,500 Ci/mmol), and is then incubated at RT for 60
minutes.


Reactions are stopped by addition of 20% phosphoric acid, and
the products are captured on P30 nitrocellulose filters and assayed for
incorporation of 33P with a BetaplateTM counter.
No enzyme and no compound control values are used to determine the
concentration of ZM447439, which gave 50% inhibition of enzyme activity.
Further details are available on request from Nicholas Keen.


Method


Cell number is evaluated by crystal violet staining. In brief, cells in
96-well plates are fixed with 1% glutaraldehyde. Then cells are stained
with 0.1% crystal violet. The unbound dye is removed by washing with
water. Bound crystal violet is solubilized with 0.2% Triton X-100. Light
extinction which increases linearly with the cell number is analyzed at
570 nm using an ELISA reader.

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Product Categories : Epigenetics > Aurora Kinase Inhibitor