Characterization of the Cellular and anti-Tumor Effects of MPI-0479605, a Small Molecule Inhibitor of the Mitotic Kinase Mps1
Menée in vitro et à l'aide de xénogreffes, cette étude évalue l'efficacité antitumorale d'une nouvelle molécule inhibant l'activité de la protéine kinase Mps1, qui est fortement exprimée durant la mitose et dans les cellules cancéreuses
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 post-mitotic checkpoint characterized by the ATR-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.
http://mct.aacrjournals.org/content/early/2011/10/06/1535-7163.MCT-11-0453.abstract