Characterization of the Cellular and Antitumor Effects of MPI-0479605, a Small-Molecule Inhibitor of the Mitotic Kinase Mps1
Open Access
- 1 December 2011
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 10 (12), 2267-2275
- https://doi.org/10.1158/1535-7163.mct-11-0453
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.Keywords
Other Versions
This publication has 36 references indexed in Scilit:
- The ATM–p53 pathway suppresses aneuploidy-induced tumorigenesisProceedings of the National Academy of Sciences of the United States of America, 2010
- Mps1 directs the assembly of Cdc20 inhibitory complexes during interphase and mitosis to control M phase timing and spindle checkpoint signalingThe Journal of cell biology, 2010
- Dissecting the role of MPS1 in chromosome biorientation and the spindle checkpoint through the small molecule inhibitor reversineThe Journal of cell biology, 2010
- Small-molecule kinase inhibitors provide insight into Mps1 cell cycle functionNature Chemical Biology, 2010
- Elevating the frequency of chromosome mis-segregation as a strategy to kill tumor cellsProceedings of the National Academy of Sciences of the United States of America, 2009
- Boveri revisited: chromosomal instability, aneuploidy and tumorigenesisNature Reviews Molecular Cell Biology, 2009
- Autophosphorylation-dependent activation of human Mps1 is required for the spindle checkpointProceedings of the National Academy of Sciences of the United States of America, 2007
- The spindle-assembly checkpoint in space and timeNature Reviews Molecular Cell Biology, 2007
- The role of apoptosis in cancer development and treatment responseNature Reviews Cancer, 2005
- Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivoCell, 1995