title: Mechanism of action of the Aurora kinase inhibitor CCT129202 and in vivo quantification of biological activity.
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 >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.
authors: Centre for Cancer Therapeutics, The Institute of Cancer Research, Cancer Research UK, 15 Cotswold Road, Belmont, Surrey SM2 5NG, United Kingdom.
authors: Florence
authors: F
authors: Chan
authors: Chongbo
authors: C
authors: Sun
authors: Meg
authors: M
authors: Perumal
authors: Quang-De
authors: QD
authors: Nguyen
authors: Vassilios
authors: V
authors: Bavetsias
authors: Edward
authors: E
authors: McDonald
authors: Vanessa
authors: V
authors: Martins
authors: Nicola E
authors: NE
authors: Wilsher
authors: Florence I
authors: FI
authors: Raynaud
authors: Melanie
authors: M
authors: Valenti
authors: Sue
authors: S
authors: Eccles
authors: Robert
authors: R
authors: Te Poele
authors: Paul
authors: P
authors: Workman
authors: Eric O
authors: EO
authors: Aboagye
authors: Spiros
authors: S
authors: Linardopoulos
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008856:Microscopy, Fluorescence; D008938:Mitosis / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C527332:CCT129202; D004791:Enzyme Inhibitors; D006657:Histones; D007093:Imidazoles; D011725:Pyridines; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases