Targeting the Mitotic Checkpoint for Cancer Therapy with NMS-P715, an Inhibitor of MPS1 Kinase
Targeting the Mitotic Checkpoint for Cancer Therapy with NMS-P715, an Inhibitor of MPS1 Kinase
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DOI：
10.1158/0008-5472.can-10-2101
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发表时间：
2010-12-15
期刊：
影响因子：
11.2
通讯作者：
Moll, Juergen
中科院分区：
文献类型：
--
作者：
Colombo, Riccardo;Caldarelli, Marina;Moll, Juergen
Mps1激酶是纺锤体组装检查点(SAC)的关键调节因子，SAC是染色体正确配对和分离所特需的有丝分裂机制。已发现它在多种人类肿瘤中异常过表达，是肿瘤细胞增殖所必需的。在这里，我们报告了NMS-P715的鉴定和特性，NMS-P715是一种选择性的口服生物利用的Mps1小分子抑制剂，它选择性地抑制癌细胞的增殖，使正常细胞几乎不受影响。NMS-P715加速有丝分裂并影响动粒成分定位，导致多种肿瘤细胞系的大量非整倍体和细胞死亡，并在临床前癌症模型中抑制肿瘤生长。抑制SAC可能代表着一种有前途的选择性靶向癌细胞的新方法。巨蟹座；70(24)；10255-。(C)2010年AACR。
MPS1 kinase is a key regulator of the spindle assembly checkpoint (SAC), a mitotic mechanism specifically required for proper chromosomal alignment and segregation. It has been found aberrantly overexpressed in a wide range of human tumors and is necessary for tumoral cell proliferation. Here we report the identification and characterization of NMS-P715, a selective and orally bioavailable MPS1 small-molecule inhibitor, which selectively reduces cancer cell proliferation, leaving normal cells almost unaffected. NMS-P715 accelerates mitosis and affects kinetochore components localization causing massive aneuploidy and cell death in a variety of tumoral cell lines and inhibits tumor growth in preclinical cancer models. Inhibiting the SAC could represent a promising new approach to selectively target cancer cells. Cancer Res; 70(24); 10255-64. (C)2010 AACR.