Inhibitors of Aurora Kinases Screened by a Chip-based Assay System

초록

Aurora kinases (AKs) are involved in cell division and thus an important target for cancer therapy. We have developed a chip-based AK assay system that can be applied to screening of a large chemical library. Two compounds, 1S-04785 and 1S-30 957, were identified as an inhibitor of AKA and AKB enzymes level and also an inhibitor of cell proliferation. Molecular docking simulation showed that the steric hindrance imposed by Asp274 of AKA and Glu161 of AKB is a determining factor of binding mode. Compared with a known inhibitor ZM447439, they had larger IC50 values for the enzymatic inhibition of AKs but comparable values in the MTT assays of cytotoxicity. HeLa cells treated with 1S-04785, 1S-30 957, and ZM447439 were all arrested at the G2/M phase. Unlike the enzyme-based assays in which the three compounds inhibited both AKA and AKB, cell-based experiments using flow cytometry and fluorescence confocal microscopy suggest that 1S-04785 inhibits AKA whereas 1S-30 957 and ZM447439 inhibit AKB.

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