ZM-447439

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

Signaling Pathways >> Cell Cycle/DNA Damage >> Aurora Kinase

Signaling Pathways >> Epigenetics >> Aurora Kinase

Research Areas >> Cancer

Aurora A:110 nM (IC50)

Aurora B:130 nM (IC50)

Cells treated with ZM-447439 progress through interphase, enter mitosis normally, and assemble bipolar spindles. However, chromosome alignment, segregation, and cytokinesis all fail. ZM-447439 inhibits cell division and inhibit mitotic phosphorylation of histone H3. ZM-447439 prevents chromosome alignment and segregation. ZM-447439 compromises spindle checkpoint function. ZM-447439 inhibits kinetochore localization of BubR1, Mad2, and Cenp-E[1]. Inhibition of Aurora kinase by ZM-447439 reduces histone H3 phosphorylation at Ser10 in Hep2 carcinoma cells. Multipolar spindles are induced in these ZM-treated G2/M-arrested cells with accumulation of 4N/8N DNA, similar to cells with genetically suppressed Aurora-B. ZM-447439 treatment induces cell apoptosis. ZM-447439 inhibition of Aurora kinase is potently in association with decrease of Akt phosphorylation at Ser473 and its substrates GSK3α/β phosphorylation at Ser21 and Ser9[2].

1 ng purified recombinant enzyme is added to a reaction cocktail containing buffer, 10 μM peptide substrate, 10 μM for Aurora A or 5 μM ATP for Aurora B, and 0.2 μCi γ[33P]ATP, and is then incubated at room temperature for 60 min. 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 Betaplate counter. No enzyme and no compound control values are used to determine the concentration of ZM-447439, which gave 50% inhibition of enzyme activity[1].

To determine cloning efficiency, MCF7 cells are plated in phenol red free DME plus 5% stripped serum, and are then treated with or without the anti-estrogen ICI 182780 at 1 μM for 48 h. ZM-447439 is then added at the indicated concentrations for 72 h. The cells are harvested, washed, and ∼400 cells plated in each well of a 6-well plate in complete media without ZM-447439. After 10 d, the colonies are fixed, stained with crystal violet, and counted. The cloning efficiency represents the number of colonies on ZM-447439-treated plates compared with DMSO-treated controls[1].

[1]. Ditchfield C, et al. 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.

[2]. Long ZJ, et al. ZM 447439 inhibition of aurora kinase induces Hep2 cancer cell apoptosis in three-dimensionalculture. Cell Cycle. 2008 May 15;7(10):1473-9.

Alisertib (MLN8237) | Tozasertib | AT9283 | Barasertib (AZD1152-HQPA) | danusertib | Hesperadin | Reversine | MLN8054 | GSK1070916 | AMG-900 | KW-2449 | TAK-632 | TAK-901 | MK-5108(VX-689) | pf-03814735