ZM447439 - CAS 331771-20-1
Catalog number: 331771-20-1
Category: Inhibitor
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Molecular Formula:
C29H31N5O4
Molecular Weight:
513.59
COA:
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Targets:
Aurora Kinase
Description:
ZM 447439 is a selective and ATP-competitive inhibitor for Aurora A and Aurora B with IC50 of 110 nM, 130 nM respectively, > 8 fold selectivity than Aurora C
Purity:
0.98
Synonyms:
Code name: ZM447439; ZM-447439; ZM 447439.
MSDS:
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InChIKey:
OGNYUTNQZVRGMN-UHFFFAOYSA-N
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)
Canonical SMILES:
COC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC=C(C=C3)NC(=O)C4=CC=CC=C4)OCCCN5CCOCC5
Current Developer:
AstraZeneca UK Ltd
1.The Aurora kinase inhibitor ZM447439 accelerates first meiosis in mouse oocytes by overriding the spindle assembly checkpoint.
Lane SI;Chang HY;Jennings PC;Jones KT Reproduction. 2010 Oct;140(4):521-30. doi: 10.1530/REP-10-0223. Epub 2010 Jul 21.
Previous studies have established that when maturing mouse oocytes are continuously incubated with the Aurora inhibitor ZM447439, meiotic maturation is blocked. In this study, we observe that by altering the time of addition of the inhibitor, oocyte maturation can actually be accelerated by 1 h as measured by the timing of polar body extrusion. ZM447439 also had the ability to overcome a spindle assembly checkpoint (SAC) arrest caused by nocodazole and so rescue polar body extrusion. Consistent with the ability of the SAC to inhibit cyclin B1 degradation by blocking activation of the anaphase-promoting complex, we could also observe a rescue in cyclin B1 degradation when ZM447439 was added to nocodazole-treated oocytes. The acceleration of the first meiotic division by ZM447439, which has not been achieved previously, and its effects on the SAC are all consistent with the proposed mitotic role of Aurora B in activating the SAC. We hypothesize that Aurora kinase activity controls the SAC in meiosis I, despite differences to the mitotic cell cycle division in spindle architecture brought about by the meiotic mono-orientation of sister kinetochores.
2.Effects of the aurora kinase inhibitors AZD1152-HQPA and ZM447439 on growth arrest and polyploidy in acute myeloid leukemia cell lines and primary blasts.
Walsby E;Walsh V;Pepper C;Burnett A;Mills K Haematologica. 2008 May;93(5):662-9. doi: 10.3324/haematol.12148. Epub 2008 Mar 26.
BACKGROUND: ;Aurora kinases play an essential role in the orchestration of chromosome separation and cytokinesis during mitosis. Small-molecule inhibition of the aurora kinases has been shown to result in inhibition of cell division, phosphorylation of histone H3 and the induction of apoptosis in a number of cell systems. These characteristics have led aurora kinase inhibitors to be considered as potential therapeutic agents.;DESIGN AND METHODS: ;Aurora kinase gene expression profiles were assessed in 101 samples from patients with acute myeloid leukemia. Subsequently, aurora kinase inhibitors were investigated for their in vitro effects on cell viability, histone H3 phosphorylation, cell cycle and morphology in acute myeloid leukemia cell lines and primary acute myeloid leukemia samples.;RESULTS: ;The aurora kinase inhibitors AZD1152-HQPA and ZM447439 induced growth arrest and the accumulation of hyperploid cells in acute myeloid leukemia cell lines and primary acute myeloid leukemia cultures. Furthermore, both agents inhibited histone H3 phosphorylation and this preceded perturbations in cell cycle and the induction of apoptosis. Single cell cloning assays were performed on diploid and polyploid cells to investigate their colony-forming capacities.
3.Aurora kinase B, epigenetic state of centromeric heterochromatin and chiasma resolution in oocytes.
Vogt E;Kipp A;Eichenlaub-Ritter U Reprod Biomed Online. 2009 Sep;19(3):352-68.
Aurora kinases comprise a family of phosphoproteins performing multiple functions in mitosis and meiosis. Because Aurora kinase B (AURKB) expression is altered in aged oocytes and there is only limited information on its function in meiosis, it was decided to study the spatial distribution and co-localization of AURKB with other regulatory proteins at centromeres during mouse oocyte maturation. AURKB associates with chromosomes after germinal vesicle breakdown, is enriched at centromeres from prometaphase I and transits to the spindle midzone at late anaphase I. Preferential inhibition of AURKB by low concentrations of ZM 447439 inhibitor prevents polar body formation and affects spindle formation and chromosome congression at meiosis I, associated with expression of BubR1 checkpoint protein at kinetochores. Release of cohesion between sister chromatids appears inhibited resulting in failure of chiasma resolution in oocytes progressing to anaphase I. Concomitantly, the inhibitor reduces histone H3 lysine 9 trimethylation at centromeric heterochromatin and affects chromosome condensation. The cytokinesis arrest protects young, healthy oocytes from errors in chromosome segregation although increasing polyploidy.
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CAS 331771-20-1 ZM447439

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