MK-5108(VX-689)

MK-5108 is a highly potent and specific inhibitor of Aurora-A kinase with an IC50 value of 0.064 nM.

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

Signaling Pathways >> Epigenetics >> Aurora Kinase

Research Areas >> Cancer

Aurora A:64 pM (IC50)

MK-5108 inhibits Aurora-A activity with an IC50 value of 0.064 nM in an ATP-competitive manner. It shows robust selectivity against the other family kinases Aurora-B (220-fold) and Aurora-C (190-fold). MK-5108 also exhibits high selectivity for Aurora-A over other protein kinases. MK-5108 inhibits the growth of 14 cell lines with IC50 values between 0.16 and 6.4 μM[1].

MK-5108 treatments at 15 and 30 mg/kg results in significant tumor growth inhibition in the HCT116 tumor model. MK-5108 is well tolerated at both doses, with minimal reduction in body weight. MK-5108 also exhibits significant antitumor activity in nude rats bearing SW48 tumors. MK-5108 at 15 and 45 mg/kg causes dose-dependent tumor growth inhibition with a %T/C of 35% and 7% at day 10, and 58% and 32% at day 27, respectively. MK-5108 is well tolerated in nude rats, with no body weight reduction and moderate effect on blood cells[1].

The Aurora-A assay reaction is conducted in the presence of 20 μM ATP, 25 μM Tetra-Kemptide, 1.0 μCi per well [γ-33P]-ATP, 0.1 ng per well Aurora-A in 50 mmol/L Tris-HCl (pH 7.4), 15 mmol/L Mg(OAc)2, and 0.2 mmol/L EDTA at 30°C for 40 min. To investigate the inhibition mode of MK-5108 for Aurora-A, the IC50 values of MK-5108 are determined in the presence of different concentrations of ATP. Then, the IC50 value is plotted as a function of ATP concentration to analyze the effect of ATP concentration on the IC50 value of MK-5108[1].

Cells are seeded in 96-well plates then incubated overnight. A medium containing MK-5108, docetaxel, or DMSO control is added and is incubated for 72 h. The cell population densities are then measured by the WST-8 colorimetric assay using a SpectraMax Plus384 plate reader. Concentration response curves are generated to give the decrease in cell population density in MK-5108– and docetaxel-treated samples relative to DMSO-treated control. Growth inhibition IC50 values are determined from those curves[1].

Rats: After 8 d, MK-5108 is suspended in 0.5% methyl cellulose/0.24% SDS and orally administered twice daily for 14 d. SW48 cells are suspended in 50% Matrigel/50% PBS and s.c. transplanted into the side flank of nude rats. After 7 d, MK-5108 is suspended in 0.5% methyl cellulose/0.24% SDS and orally administered twice daily for 2 d/wk for 3 wk. In a HeLa-luc and ES-2 dual flank xenograft model, HeLa-luc or ES-2 cells are suspended in 50% Matrigel and 50% PBS, and s.c. transplanted into the right or left side flank of nude rats. After 8 d, vehicle (5% ethanol-saline) or 7.5 mg/kg docetaxel is injected i.v. MK-5108 is orally administered twice daily for 2 d 24 h after the docetaxel injection. The volume of each tumor is determined from the tumor diameter[1].

[1]. Shimomura T, et al. MK-5108, a highly selective Aurora-A kinase inhibitor, shows antitumor activity alone and in combination with docetaxel. Mol Cancer Ther. 2010 Jan;9(1):157-66.

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