Aurora-A kinase is a one of the key regulators during mitosis progression, whose overexpression is frequently observed in some human cancers, and results in aberrant mitosis leading to chromosomal instability and possibly tumorigenesis. MK-5108 specifically inhibited Aurora-A activity with an IC50 value of 0.064 nM in an ATP-competitive manner. In synchronized HeLa-S3 cells, accumulation of pHH3-positive cells was observed by treatment with MK-5108 at concentrations between 300 nM and 10 μM, suggesting the selective inhibition of Aurora-A. DNA profiles of asynchronously cultured HeLa-S3 cells treated by MK-5108 for 24 h were evaluated by flow cytometry. Consistent with the induction of pHH3-positive cells, MK-5108 induced accumulation of cells in the G2-M phase. After oral administration of MK-5108 at 16 mg/kg with a HeLa-luc xenograft rat model, MK-5108 treatment resulted in the induction of pHH3 in tumor and skin tissues, which started at 2 hours and reached a maximum at 4 hours. Treatments with oral MK-5108 twice daily for 12 days at 15 and 30 mg/kg resulted in significant tumor growth inhibition in SCID mice bearing HCT116 tumors[3].
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