Targeting the Mitotic Checkpoint for Cancer Therapy with NMS-P715, an Inhibitor of MPS1 Kinase

被引：151

作者：

Colombo, Riccardo ^{[1
]}

Caldarelli, Marina ^{[1
]}

Mennecozzi, Milena ^{[1
]}

Giorgini, Maria Laura ^{[1
]}

Sola, Francesco ^{[1
]}

Cappella, Paolo ^{[1
]}

Perrera, Claudia ^{[1
]}

Depaolini, Stefania Re ^{[1
]}

Rusconi, Luisa ^{[1
]}

Cucchi, Ulisse ^{[1
]}

Avanzi, Nilla ^{[1
]}

Bertrand, Jay Aaron ^{[1
]}

Bossi, Roberto Tiberio ^{[1
]}

Pesenti, Enrico ^{[1
]}

Galvani, Arturo ^{[1
]}

Isacchi, Antonella ^{[1
]}

Colotta, Francesco ^{[1
]}

Donati, Daniele ^{[1
]}

Moll, Juergen ^{[1
]}

机构：

[1] Nerviano Med Sci Srl Oncol, I-20014 Nerviano, Italy

来源：

CANCER RESEARCH | 2010年 / 70卷 / 24期

关键词：

SPINDLE-ASSEMBLY CHECKPOINT; POLE BODY DUPLICATION; CHROMOSOMAL INSTABILITY; EXTRA CENTROSOMES; HUMAN-CELLS; ANEUPLOIDY; EXPRESSION; GENES; KINETOCHORE; CARCINOMA;

D O I：

10.1158/0008-5472.CAN-10-2101

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：10255 / 10264

页数：10

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