Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase

被引：365

作者：

Manfredi, Mark G. ^{[1
]}

Ecsedy, Jeffrey A. ^{[1
]}

Meetze, Kristan A. ^{[1
]}

Balani, Suresh K. ^{[1
]}

Burenkova, Olga ^{[1
]}

Chen, Wei ^{[1
]}

Galvin, Katherine M. ^{[1
]}

Hoar, Kara M. ^{[1
]}

Huck, Jessica J. ^{[1
]}

LeRoy, Patrick J. ^{[1
]}

Ray, Emily T. ^{[1
]}

Sells, Todd B. ^{[1
]}

Stringer, Bradley ^{[1
]}

Stroud, Stephen G. ^{[1
]}

Vos, Tricia J. ^{[1
]}

Weatherhead, Gabriel S. ^{[1
]}

Wysong, Deborah R. ^{[1
]}

Zhang, Mengkun ^{[1
]}

Bolen, Joseph B. ^{[1
]}

Claiborne, Christopher F. ^{[1
]}

机构：

[1] Millennium Pharmaceut Inc, Dept Oncol, Cambridge, MA 02139 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2007年 / 104卷 / 10期

关键词：

cancer; mitosis; apoptosis;

D O I：

10.1073/pnas.0608798104

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Increased Aurora A expression occurs in a variety of human cancers and induces chromosomal abnormalities during mitosis associated with tumor initiation and progression. MLN8054 is a selective small-molecule Aurora A kinase inhibitor that has entered Phase I clinical trials for advanced solid tumors. MLN8054 inhibits recombinant Aurora A kinase activity in vitro and is selective for Aurora A over the family member Aurora B in cultured cells. MLN8054 treatment results in G(2)/M accumulation and spindle defects and inhibits proliferation in multiple cultured human tumor cells lines. Growth of human tumor xenografts in nude mice was dramatically inhibited after oral administration of MLN8054 at well tolerated doses. Moreover, the tumor growth inhibition was sustained after discontinuing MLN8054 treatment. In human tumor xenografts, MLN8054 induced mitotic accumulation and apoptosis, phenotypes consistent with inhibition of Aurora A. MLN8054 is a selective inhibitor of Aurora A kinase that robustly inhibits growth of human tumor xenografts and represents an attractive modality for therapeutic intervention of human cancers.

引用

页码：4106 / 4111

页数：6

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