The Aurora family of
serine/threonine kinases is 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. Increased levels of
Aurora kinases have also been linked to a broad range of human
tumors. Here, we describe the properties of
CCT129202, a representative of a structurally novel series of
imidazopyridine small-molecule inhibitors of
Aurora kinase activity. This compound showed high selectivity for the
Aurora kinases over a panel of other
kinases tested and inhibits proliferation in multiple cultured human tumor cell lines.
CCT129202 causes the accumulation of human
tumor cells with >or=4N
DNA content, leading to apoptosis. CCT120202-treated human
tumor cells showed a delay in mitosis, abrogation of
nocodazole-induced mitotic arrest, and spindle defects. Growth of HCT116 xenografts in nude mice was inhibited after i.p. administration of
CCT129202. We show that p21, the
cyclin-dependent kinase inhibitor, is induced by
CCT129202. Up-regulation of p21 by
CCT129202 in HCT116 cells led to Rb hypophosphorylation and E2F inhibition, contributing to a decrease in
thymidine kinase 1 transcription. This has facilitated the use of 3'-deoxy-3'[(18)F]fluorothymidine-positron emission tomography to measure noninvasively the
biological activity of the
Aurora kinase inhibitor
CCT129202 in vivo.