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.

Cell lines	BON, QGP-1 and MIP-101 cells
Concentrations	0-5 μM
Incubation Time	72 hours
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.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Baboon	Dog	Monkey	Rabbit	Guinea pig	Rat	Hamster	Mouse
Weight (kg)	12	10	3	1.8	0.4	0.15	0.08	0.02
Body Surface Area (m2)	0.6	0.5	0.24	0.15	0.05	0.025	0.02	0.007
Km factor	20	20	12	12	8	6	5	3

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×	mouse Km(3)	= 11.2 mg/kg
	rat Km(6)

Chemical Information

Molecular Weight (MW)	513.59
Formula	C29H31N5O4
CAS No.	331771-20-1

Storage	3 years -20℃Powder
	6 months-80℃in solvent (DMSO, water, etc.)
Synonyms

Solubility (25°C) *	In vitro	DMSO	103 mg/mL (200.54 mM)
		Water	<1 mg/mL (
		Ethanol	<1 mg/mL (
	In vivo	30% PEG400/0.5% Tween80/5% propylene glycol	30 mg/mL
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Name	N-(4-(6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-ylamino)phenyl)benzamide

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Product Categories : Epigenetics > Aurora Kinase Inhibitor