Targeting the mitotic checkpoint for cancer therapy with NMS-P715, an inhibitor of MPS1 kinase

R Colombo, M Caldarelli, M Mennecozzi, ML Giorgini… - Cancer research, 2010 - AACR
R Colombo, M Caldarelli, M Mennecozzi, ML Giorgini, F Sola, P Cappella, C Perrera…
Cancer research, 2010AACR
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 …
Abstract
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. ©2010 AACR.
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