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Research Articles: Therapeutics, Targets, and Development

Mechanism of action of the Aurora kinase inhibitor CCT129202 and in vivo quantification of biological activity

¹ Cancer Research UK, Centre for Cancer Therapeutics, The Institute of Cancer Research, Belmont, Surrey, United Kingdom; ² Molecular Therapy, Imperial College London, Faculty of Medicine Hammersmith Hospital, and ³ Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom

Requests for reprints: Spiros Linardopoulos, Centre for Cancer Therapeutics, The Institute of Cancer Research, Cancer Research UK, 15 Cotswold Road, Belmont, Surrey SM2 5NG, United Kingdom. Phone: 44-208-722-4133; Fax: 44-207-153-5340. E-mail: spiros.linardopoulos{at}icr.ac.uk

Abstract

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 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'[¹⁸F]fluorothymidine-positron emission tomography to measure noninvasively the biological activity of the Aurora kinase inhibitor CCT129202 in vivo. [Mol Cancer Ther 2007;6(12):3147–57]

Grant support: Programme grants from Cancer Research UK (C309/A8274 and C2536/A5708) and Breakthrough Breast Cancer.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 10/ 2/07; accepted 11/ 1/07.