ZM 447439

Aurora Kinase inhibitor,potent and selective CAS# 331771-20-1

ZM 447439

Catalog No. BCC2169----Order now to get a substantial discount!

Product Name & Size Price Stock
ZM 447439: 5mg $46 In Stock
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Chemical structure

ZM 447439

3D structure

Chemical Properties of ZM 447439

Cas No. 331771-20-1 SDF Download SDF
PubChem ID 9914412 Appearance Powder
Formula C29H31N5O4 M.Wt 513.59
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 100 mg/mL (194.71 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name N-[4-[[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino]phenyl]benzamide
SMILES COC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC=C(C=C3)NC(=O)C4=CC=CC=C4)OCCCN5CCOCC5
Standard InChIKey OGNYUTNQZVRGMN-UHFFFAOYSA-N
Standard InChI InChI=1S/C29H31N5O4/c1-36-26-18-24-25(19-27(26)38-15-5-12-34-13-16-37-17-14-34)30-20-31-28(24)32-22-8-10-23(11-9-22)33-29(35)21-6-3-2-4-7-21/h2-4,6-11,18-20H,5,12-17H2,1H3,(H,33,35)(H,30,31,32)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of ZM 447439

DescriptionNovel, selective ATP-competitive inhibitor of Aurora B kinase in vitro (IC50 values are 50, 250 and 1000 nM for Aurora B, C and A kinases respectively). Selective over a range of other kinases including cdk1 and PLK1 (IC50 > 10 μM). Inhibits cell division and displays selective toxicity towards proliferating tumor cells versus non-dividing cells.

ZM 447439 Dilution Calculator

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ZM 447439 Molarity Calculator

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Preparing Stock Solutions of ZM 447439

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.9471 mL 9.7354 mL 19.4708 mL 38.9416 mL 48.677 mL
5 mM 0.3894 mL 1.9471 mL 3.8942 mL 7.7883 mL 9.7354 mL
10 mM 0.1947 mL 0.9735 mL 1.9471 mL 3.8942 mL 4.8677 mL
50 mM 0.0389 mL 0.1947 mL 0.3894 mL 0.7788 mL 0.9735 mL
100 mM 0.0195 mL 0.0974 mL 0.1947 mL 0.3894 mL 0.4868 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on ZM 447439

ZM 447439 is a novel, potent and selective inhibitor of Aurora kinase, a family of serine/threonine kinases essential for accurate chromosome segregation during cell division, that inhibits the activity of purified recombinant Aurora A and Aurora B proteins in vitro with 50% inhibition concentration IC50 values of 110 nM and 130 nM respectively and hence inhibits phosphorylation of histone H3 on serine 10. Being specifically for Aurora kinases, ZM 447439 barely inhibits the majority of other protein kinases (IC50 > 10 μM), such as CDK1/2/4, IKK1/2, PLK1, CHK1, cFLT2, KDR2, FAK and Zap-70, except for MEK1, SRC and LCK (IC50 values of 1.79 μM, 1.03 and 0.88 μM respectively μM).

Reference

Li M, Jung A, Ganswindt U, Marini P, Friedl A, Daniel PT, Lauber K, Jendrossek V, Belka C. Aurora kinase inhibitor ZM447439 induces apoptosis via mitochondrial pathways. Biochem Pharmacol. 2010 Jan 15;79(2):122-9. doi: 10.1016/j.bcp.2009.08.011. Epub 2009 Aug 15.

Ditchfield C, Johnson VL, Tighe A, Ellston R, Haworth C, Johnson T, Mortlock A, Keen N, Taylor SS. Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores. J Cell Biol. 2003 Apr 28;161(2):267-80.

Long ZJ, Xu J, Yan M, Zhang JG, Guan Z, Xu DZ, Wang XR, Yao J, Zheng FM, Chu GL, Cao JX, Zeng YX, Liu Q. ZM 447439 inhibition of aurora kinase induces Hep2 cancer cell apoptosis in three-dimensional culture. Cell Cycle. 2008 May 15;7(10):1473-9. Epub 2008 Mar 12.

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References on ZM 447439

ZM 447439 inhibition of aurora kinase induces Hep2 cancer cell apoptosis in three-dimensional culture.[Pubmed:18418083]

Cell Cycle. 2008 May 15;7(10):1473-9.

Mitotic Aurora kinases are essential for accurate chromosome segregation during cell division. Forced overexpression of Aurora kinase results in centrosome amplification and multipolar spindles, causing aneuploidy, a hallmark of cancer. ZM447439 (ZM), an Aurora selective ATP-competitive inhibitor, interferes with the spindle integrity checkpoint and chromosome segregation. Here, we showed that inhibition of Aurora kinase by ZM reduced histone H3 phosphorylation at Ser10 in Hep2 carcinoma cells. Multipolar spindles were induced in these ZM-treated G(2)/M-arrested cells with accumulation of 4N/8N DNA, similar to cells with genetically suppressed Aurora-B. Cells subsequently underwent apoptosis, as assessed by cleavage of critical apoptotic associated protein PARP. Hep2 cells formed a tumor-like cell mass in 3-dimensional matrix culture; inhibition of Aurora kinase by ZM either destructed the preformed cell mass or prevented its formation, by inducing apoptotic cell death as stained for cleaved caspase-3. Lastly, ZM inhibition of Aurora kinase was potently in association with decrease of Akt phosphorylation at Ser473 and its substrates GSK3alpha/beta phosphorylation at Ser21 and Ser9. Together, we demonstrated that Aurora kinase served as a potential molecular target of ZM for more selective therapeutic cancer treatment.

Validating Aurora B as an anti-cancer drug target.[Pubmed:16912073]

J Cell Sci. 2006 Sep 1;119(Pt 17):3664-75.

The Aurora kinases, a family of mitotic regulators, have received much attention as potential targets for novel anti-cancer therapeutics. Several Aurora kinase inhibitors have been described including ZM447439, which prevents chromosome alignment, spindle checkpoint function and cytokinesis. Subsequently, ZM447439-treated cells exit mitosis without dividing and lose viability. Because ZM447439 inhibits both Aurora A and B, we set out to determine which phenotypes are due to inhibition of which kinase. Using molecular genetic approaches, we show that inhibition of Aurora B kinase activity phenocopies ZM447439. Furthermore, a novel ZM compound, which is 100 times more selective for Aurora B over Aurora A in vitro, induces identical phenotypes. Importantly, inhibition of Aurora B kinase activity induces a penetrant anti-proliferative phenotype, indicating that Aurora B is an attractive anti-cancer drug target. Using molecular genetic and chemical-genetic approaches, we also probe the role of Aurora A kinase activity. We show that simultaneous repression of Aurora A plus induction of a catalytic mutant induces a monopolar phenotype. Consistently, another novel ZM-related inhibitor, which is 20 times as potent against Aurora A compared with ZM447439, induces a monopolar phenotype. Expression of a drug-resistant Aurora A mutant reverts this phenotype, demonstrating that Aurora A kinase activity is required for spindle bipolarity in human cells. Because small molecule-mediated inhibition of Aurora A and Aurora B yields distinct phenotypes, our observations indicate that the Auroras may present two avenues for anti-cancer drug discovery.

Discovery of novel and potent thiazoloquinazolines as selective Aurora A and B kinase inhibitors.[Pubmed:16451062]

J Med Chem. 2006 Feb 9;49(3):955-70.

The synthesis of a novel series of quinazolines substituted at C4 by five-membered ring aminoheterocycles is reported. Their in vitro structure-activity relationships versus Aurora A and B serine-threonine kinases is discussed. Our results demonstrate that quinazolines with a substituted aminothiazole at C4 possess potent Aurora A and B inhibitory activity and excellent selectivity against a panel of various serine-threonine and tyrosine kinases, as exemplified by compound 46. We found also that the position and nature of the substituent on the thiazole play key roles in cellular potency. Compounds with an acetanilide substituent at C5' have the greatest cellular activity. The importance of the C5' position for substitution has been rationalized by ab initio molecular orbital calculations. Results show that the planar conformation with the sulfur of the thiazole next to the quinazoline N-3 is strongly favored over the other possible planar conformation. Compound 46 is a potent suppressor of the expression of phospho-histone H3 in tumor cells in vitro as well as in vivo, where 46, administered as its phosphate prodrug 54, suppresses the expression of phospho-histone H3 in subcutaneously implanted tumors in nude mice.

Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores.[Pubmed:12719470]

J Cell Biol. 2003 Apr 28;161(2):267-80.

The Aurora/Ipl1 family of protein kinases plays multiple roles in mitosis and cytokinesis. Here, we describe ZM447439, a novel selective Aurora kinase inhibitor. Cells treated with ZM447439 progress through interphase, enter mitosis normally, and assemble bipolar spindles. However, chromosome alignment, segregation, and cytokinesis all fail. Despite the presence of maloriented chromosomes, ZM447439-treated cells exit mitosis with normal kinetics, indicating that the spindle checkpoint is compromised. Indeed, ZM447439 prevents mitotic arrest after exposure to paclitaxel. RNA interference experiments suggest that these phenotypes are due to inhibition of Aurora B, not Aurora A or some other kinase. In the absence of Aurora B function, kinetochore localization of the spindle checkpoint components BubR1, Mad2, and Cenp-E is diminished. Furthermore, inhibition of Aurora B kinase activity prevents the rebinding of BubR1 to metaphase kinetochores after a reduction in centromeric tension. Aurora B kinase activity is also required for phosphorylation of BubR1 on entry into mitosis. Finally, we show that BubR1 is not only required for spindle checkpoint function, but is also required for chromosome alignment. Together, these results suggest that by targeting checkpoint proteins to kinetochores, Aurora B couples chromosome alignment with anaphase onset.

Description

ZM-447439 is an aurora kinase inhibitor with IC50s of 110 and 130 nM for aurora A and B, respectively.

Keywords:

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