ZM447439

Biological Activity

ZM447439 is an Aurora kinase B inhibitor, suppresses the growth of cervical cancer SiHa cells and enhances the chemosensitivity to cisplatin. Aurora family kinases play roles in several mitotic processes, including the G2/M transition, mitotic spindle organization, chromosome segregation, and cytokinesis. ZM447439 has dramatic effects on chromosome morphology and spindle dynamics. ZM-447439 can reduce the number of SiHa cells, increase the volume of cells and lead to apoptosis. The growth of SiHa cells treated with ZM447439 was inhibited in dose- and time-dependent manners. ZM447439 significantly inhibited the expression of Aurora-B and H3-P protein (P < 0.05). ZM-447439 selectively over a range of other kinases such as Cdk1 and PLK1 (up to 10mM). Additionally, aurora kinase inhibition by ZM447439 potently induced apoptosis, which was accompanied by DNA fragmentation and caspase 3 and 7 activation.

Customer Product Validations & Biological Datas

	Source	Concordia University (2015). Figure 9. ZM447439 (Abmole Bioscience)
	Method	Inhibit Aurora B kinase
	Cell Lines	MDCK cell lines
	Concentrations	1 μM
	Incubation Time	20-­‐40 min
	Results	Upon treating MDCK cells with an 35 Aurora B inhibitor, ZM447439, we found that the number asymmetrically ingressing cells was not statistically changed in comparison to control cells

Protocol

Cell Experiment
Cell lines	MCF7 cells
Preparation method	Cell cycle analysis and cloning assays. DNA content and mitotic index measurements and synchronization of TA-HeLa cells at G1/S using a double thymidine block were done as described previously (Taylor and McKeon, 1997). To determine cloning efficiency, MCF7 cells were plated in phenol red free DME plus 5% stripped serum (HyClone), and were then treated with or without the anti-estrogen ICI 182780 at 1 μM for 48 h. ZM447439 was then added at the indicated concentrations for 72 h. The cells were harvested, washed, and ∼400 cells plated in each well of a 6-well plate in complete media without ZM447439. After 10 d, the colonies were fixed, stained with crystal violet, and counted. The cloning efficiency represents the number of colonies on ZM447439-treated plates compared with DMSO-treated controls.
Concentrations	0~5 μM
Incubation time	72 h

Animal Experiment
Animal models	MOLM13 cells in murine xenograft model
Formulation	3 M Tris, pH 9.0, at a concentration of 2.5 mg/mL
Dosages	5 mg/kg 4 times a week for 2 weeks
Administration	intraperitoneal injection

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

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

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

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

Chemical Information

References

[1] Georgieva I, et al. Neuroendocrinology. ZM447439, a novel promising aurora kinase inhibitor, provokes antiproliferative and proapoptotic effects alone and in combination with bio- and chemotherapeutic agents in gastroenteropancreatic neuroendocrine tumor cell lines.