MK-5108, a Highly Selective Aurora-A Kinase Inhibitor, Shows Antitumor Activity Alone and in Combination with Docetaxel

被引：102

作者：

Shimomura, Toshiyasu ^{[1
]}

Hasako, Shinichi ^{[1
]}

Nakatsuru, Yoko ^{[2
]}

Mita, Takashi ^{[3
]}

Ichikawa, Koji ^{[1
]}

Kodera, Tsutomu ^{[2
]}

Sakai, Takumi ^{[2
]}

Nambu, Tadahiro ^{[2
]}

Miyamoto, Mayu ^{[1
]}

Takahashi, Ikuko ^{[1
]}

Miki, Satomi ^{[1
]}

Kawanishi, Nobuhiko ^{[3
]}

Ohkubo, Mitsuru ^{[3
]}

Kotani, Hidehito ^{[1
]}

Iwasawa, Yoshikazu ^{[3
]}

机构：

[1] Merck Res Labs, Banyu Tsukuba Res Inst, Dept Oncol, Tsukuba, Ibaraki 3002611, Japan

[2] Merck Res Labs, Banyu Tsukuba Res Inst, Dept Pharmacol, Tsukuba, Ibaraki 3002611, Japan

[3] Merck Res Labs, Banyu Tsukuba Res Inst, Dept Chem, Tsukuba, Ibaraki 3002611, Japan

来源：

MOLECULAR CANCER THERAPEUTICS | 2010年 / 9卷 / 01期

关键词：

SPINDLE ASSEMBLY CHECKPOINT; SMALL-MOLECULE INHIBITOR; SQUAMOUS-CELL CARCINOMA; SUPPRESSES TUMOR-GROWTH; CANCER CELLS; B KINASE; OVEREXPRESSION; CHEMOSENSITIVITY; TRANSFORMATION; AMPLIFICATION;

D O I：

10.1158/1535-7163.MCT-09-0609

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. Mol Cancer Ther; 9(1); 157-66. (C) 2010 AACR.

引用

页码：157 / 166

页数：10

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