Supplementary Tables 1-2, Figures 1-7 from Characterization of the Cellular and Antitumor Effects of MPI-0479605, a Small-Molecule Inhibitor of the Mitotic Kinase Mps1

Tardif, Keith D.; Rogers, Aaron; Cassiano, Jared; Roth, Bruce L.; Cimbora, Daniel M.; McKinnon, Rena; Peterson, Ashley; Douce, Thomas B.; Robinson, Rosann; Dorweiler, Irene; Davis, Thaylon; Hess, Mark A.; Ostanin, Kirill; Papac, Damon I.; Baichwal, Vijay; McAlexander, Ian; Willardsen, J. Adam; Saunders, Michael; Christophe, Hoarau; Kumar, D. Vijay; Wettstein, Daniel A.; Carlson, Robert O.; Williams, Brandi L.

doi:10.1158/1535-7163.22497223.v1

Supplementary Tables 1-2, Figures 1-7 from Characterization of the Cellular and Antitumor Effects of MPI-0479605, a Small-Molecule Inhibitor of the Mitotic Kinase Mps1

journal contribution

posted on 2023-04-03, 13:27 authored by Keith D. Tardif, Aaron Rogers, Jared Cassiano, Bruce L. Roth, Daniel M. Cimbora, Rena McKinnon, Ashley Peterson, Thomas B. Douce, Rosann Robinson, Irene Dorweiler, Thaylon Davis, Mark A. Hess, Kirill Ostanin, Damon I. Papac, Vijay Baichwal, Ian McAlexander, J. Adam Willardsen, Michael Saunders, Hoarau Christophe, D. Vijay Kumar, Daniel A. Wettstein, Robert O. Carlson, Brandi L. Williams

PDF file - 123K

History

ARTICLE ABSTRACT

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. ©2011 AACR.

Usage metrics

Keywords

Drug Mechanisms Cell cycle mechanisms of anticancer drug action Drug-mediated stimulation of cell death pathways p53 and anticancer drug action Drug Targets Preclinical Models Xenograft models

Licence

CC BY

Supplementary Tables 1-2, Figures 1-7 from Characterization of the Cellular and Antitumor Effects of MPI-0479605, a Small-Molecule Inhibitor of the Mitotic Kinase Mps1

History

ARTICLE ABSTRACT

Usage metrics

Categories

Keywords

Licence

Exports