Characterization of CCT129202, a novel Aurora kinase inhibitor and in vivo quantification of biological activity

A239 The Aurora family of serine/threonine kinases are important for the regulation of centrosome maturation, chromosome segregation and cytokinesis during mitosis. Overexpression of Aurora kinases in mammalian cells leads to genetic instability and transformation. We developed and characterised the mechanism of action of CCT129202, a small molecule inhibitor of Aurora kinase activity. CCT129202 inhibits Aurora kinases with an IC50 of 50 nM, inhibits growth of a panel of human tumour cell lines with GI50 between 0.1 μM - 1 μM and induced accumulation of tumour cells with 4N DNA content. CCT129202 delays the cell cycle in mitosis and abrogates nocodazole-induced mitotic arrest. HeLa cells treated with CCT129202 showed formation of abnormal mitotic spindles leading to cell death. In xenografts in nude mouse models, this compound is a potent inhibitor of tumour growth and downregulates histone H3 phosphorylation. Finally, we used [18F]fluorothymidine-positron emission tomography to measure non-invasively the biological activity of the Aurora kinase inhibitor CCT129202 in vivo.