Mechanism of action of the Aurora kinase inhibitor CCT129202 and in vivo quantification of biological activity.
Publication Date
2007-12ICR Author
Author
Chan, F
Sun, C
Perumal, M
Nguyen, QD
Bavetsias, V
McDonald, E
Martins, V
Wilsher, NE
Raynaud, FI
Valenti, M
Eccles, S
Te Poele, R
Workman, P
Aboagye, EO
Linardopoulos, S
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Version of record
Subject
Cell Line, Tumor
Animals
Humans
Mice
Imidazoles
Pyridines
Protein-Serine-Threonine Kinases
Retinoblastoma Protein
Histones
Enzyme Inhibitors
Microscopy, Fluorescence
Enzyme-Linked Immunosorbent Assay
Oligonucleotide Array Sequence Analysis
Mitosis
Apoptosis
Down-Regulation
Phosphorylation
Female
Tumor Suppressor Protein p53
Aurora Kinases
Research team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Drug Target Discovery
Medicinal Chemistry 1 (including Analytical Chemistry)
Tumour Biology & Metastasis
Language
eng
License start date
2007-12
Citation
Molecular cancer therapeutics, 2007, 6 (12 Pt 1), pp. 3147 - 3157