Myrexis, Inc. Salt Lake City, Utah, USA.
Mol Cancer Ther. 2011 Dec;10(12):2267-75. doi: 10.1158/1535-7163.MCT-11-0453. Epub 2011 Oct 6.
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.
Mps1 是一种双特异性蛋白激酶，对于染色体的双极附着到有丝分裂纺锤体以及维持纺锤体组装检查点至关重要，直到所有染色体都正确附着。Mps1 在有丝分裂期间表达水平较高，在癌细胞中大量表达。Mps1 功能的破坏会诱导非整倍体和细胞死亡。我们报告了 MPI-0479605 的鉴定，这是一种有效的、选择性的 Mps1 ATP 竞争抑制剂。用 MPI-0479605 处理的细胞经历异常有丝分裂，导致非整倍体和微核形成。在野生型 p53 的细胞中，这会促进有丝分裂后检查点的诱导，其特征是 ATM 和 RAD3 相关蛋白依赖性激活 p53-p21 途径。在野生型和 p53 突变细胞系中，会发生生长停滞和 DNA 合成抑制。随后，细胞经历有丝分裂灾难和/或凋亡反应。在异种移植模型中，MPI-0479605 抑制肿瘤生长，表明靶向 Mps1 的药物可能具有作为新型癌症治疗剂的用途。
