Abstract |
Aurora-A kinase is a one of the key regulators during mitosis progression. Aurora-A kinase is a potential target for anticancer therapies because overexpression of Aurora-A, which is frequently observed in some human cancers, results in aberrant mitosis leading to chromosomal instability and possibly tumorigenesis. MK-5108 is a novel small molecule with potent inhibitory activity against Aurora-A kinase. Although most of the Aurora-kinase inhibitors target both Aurora-A and Aurora-B, MK-5108 specifically inhibited Aurora-A kinase in a panel of protein kinase assays. Inhibition of Aurora-A by MK-5108 in cultured cells induced cell cycle arrest at the G(2)-M phase in flow cytometry analysis. The effect was confirmed by the accumulation of cells with expression of phosphorylated Histone H3 and inhibition of Aurora-A autophosphorylation by immunostaining assays. MK-5108 also induced phosphorylated Histone H3 in skin and xenograft tumor tissues in a nude rat xenograft model. MK-5108 inhibited growth of human tumor cell lines in culture and in different xenograft models. Furthermore, the combination of MK-5108 and docetaxel showed enhanced antitumor activities compared with control and docetaxel alone-treated animals without exacerbating the adverse effects of docetaxel. MK-5108 is currently tested in clinical trials and offers a new therapeutic approach to combat human cancers as a single agent or in combination with existing taxane therapies.
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Authors | Toshiyasu Shimomura, Shinichi Hasako, Yoko Nakatsuru, Takashi Mita, Koji Ichikawa, Tsutomu Kodera, Takumi Sakai, Tadahiro Nambu, Mayu Miyamoto, Ikuko Takahashi, Satomi Miki, Nobuhiko Kawanishi, Mitsuru Ohkubo, Hidehito Kotani, Yoshikazu Iwasawa |
Journal | Molecular cancer therapeutics
(Mol Cancer Ther)
Vol. 9
Issue 1
Pg. 157-66
(Jan 2010)
ISSN: 1538-8514 [Electronic] United States |
PMID | 20053775
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 4-(3-chloro-2-fluorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin to 2-yl)methyl) cyclohexanecarboxylic acid
- Antineoplastic Agents
- Cyclohexanecarboxylic Acids
- Protein Kinase Inhibitors
- Taxoids
- Thiazoles
- Docetaxel
- AURKB protein, human
- Aurka protein, mouse
- Aurka protein, rat
- Aurkb protein, mouse
- Aurkb protein, rat
- Aurora Kinase A
- Aurora Kinase B
- Aurora Kinases
- Protein Serine-Threonine Kinases
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Topics |
- Animals
- Antineoplastic Agents
(administration & dosage, chemistry, pharmacology)
- Antineoplastic Combined Chemotherapy Protocols
(pharmacology)
- Aurora Kinase A
- Aurora Kinase B
- Aurora Kinases
- Cell Death
(drug effects)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Cyclohexanecarboxylic Acids
(administration & dosage, chemistry, pharmacology)
- Docetaxel
- Humans
- Inhibitory Concentration 50
- Mice
- Mitosis
(drug effects)
- Protein Kinase Inhibitors
(administration & dosage, chemistry, pharmacology)
- Protein Serine-Threonine Kinases
(antagonists & inhibitors)
- Rats
- Taxoids
(pharmacology, toxicity)
- Thiazoles
(administration & dosage, chemistry, pharmacology)
- Xenograft Model Antitumor Assays
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