Characterization of the Cellular and Antitumor Effects of MPI-0479605, a Small-Molecule Inhibitor of the Mitotic Kinase Mps1

被引：86

作者：

Tardif, Keith D. ^{[1
]}

Rogers, Aaron ^{[1
]}

Cassiano, Jared ^{[1
]}

Roth, Bruce L. ^{[1
]}

Cimbora, Daniel M. ^{[1
]}

McKinnon, Rena ^{[1
]}

Peterson, Ashley ^{[1
]}

Douce, Thomas B. ^{[1
]}

Robinson, Rosann ^{[1
]}

Dorweiler, Irene ^{[1
]}

Davis, Thaylon ^{[1
]}

Hess, Mark A. ^{[1
]}

Ostanin, Kirill ^{[1
]}

Papac, Damon I. ^{[1
]}

Baichwal, Vijay ^{[1
]}

McAlexander, Ian ^{[1
]}

Willardsen, J. Adam ^{[1
]}

Saunders, Michael ^{[1
]}

Christophe, Hoarau ^{[1
]}

Kumar, D. Vijay ^{[1
]}

Wettstein, Daniel A. ^{[1
]}

Carlson, Robert O. ^{[1
]}

Williams, Brandi L. ^{[1
]}

机构：

[1] Myrexis Inc, Salt Lake City, UT USA

来源：

MOLECULAR CANCER THERAPEUTICS | 2011年 / 10卷 / 12期

关键词：

CENP-E; CHROMOSOME ALIGNMENT; SPINDLE CHECKPOINT; HISTONE H2AX; IONIZING-RADIATION; CANCER-THERAPY; SERINE; 139; PHOSPHORYLATION; CELLS; KINETOCHORES;

D O I：

10.1158/1535-7163.MCT-11-0453

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Mps1 is a dual specificity protein kinase that is essential for the bipolar attachment of chromosomes to the mitotic spindle and for maintaining the spindle assembly checkpoint until all chromosomes are properly attached. Mps1 is expressed at high levels during mitosis and is abundantly expressed in cancer cells. Disruption of Mps1 function induces aneuploidy and cell death. We report the identification of MPI-0479605, a potent and selective ATP competitive inhibitor of Mps1. Cells treated with MPI-0479605 undergo aberrant mitosis, resulting in aneuploidy and formation of micronuclei. In cells with wild-type p53, this promotes the induction of a postmitotic checkpoint characterized by the ATM- and RAD3-related-dependent activation of the p53-p21 pathway. In both wild-type and p53 mutant cells lines, there is a growth arrest and inhibition of DNA synthesis. Subsequently, cells undergo mitotic catastrophe and/or an apoptotic response. In xenograft models, MPI-0479605 inhibits tumor growth, suggesting that drugs targeting Mps1 may have utility as novel cancer therapeutics. Mol Cancer Ther; 10(12); 2267-75. (C)2011 AACR.

引用

页码：2267 / 2275

页数：9

共 37 条

[1] Phosphorylation by p34(cdc2) regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo [J].