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

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.

[1]  Taebo Sim,et al.  Small Molecule Kinase Inhibitors Provide Insight into Mps1 Cell Cycle Function , 2010, Nature chemical biology.

[2]  R. Medema,et al.  Elevating the frequency of chromosome mis-segregation as a strategy to kill tumor cells , 2009, Proceedings of the National Academy of Sciences.

[3]  D. Cleveland,et al.  Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis , 2009, Nature Reviews Molecular Cell Biology.

[4]  P. Kaestner,et al.  Determinants for the efficiency of anticancer drugs targeting either Aurora-A or Aurora-B kinases in human colon carcinoma cells , 2009, Molecular Cancer Therapeutics.

[5]  A. Amon,et al.  Aneuploidy: cancer's fatal flaw? , 2009, Cancer research.

[6]  B. Weaver,et al.  The role of aneuploidy in promoting and suppressing tumors , 2009, The Journal of cell biology.

[7]  Hongtao Yu,et al.  Pharmacologic abrogation of the mitotic spindle checkpoint by an indolocarbazole discovered by cellular screening efficiently kills cancer cells. , 2009, Cancer research.

[8]  Ji Luo,et al.  Principles of Cancer Therapy: Oncogene and Non-oncogene Addiction , 2009, Cell.

[9]  D. Cleveland,et al.  Unattached kinetochores catalyze production of an anaphase inhibitor that requires a Mad2 template to prime Cdc20 for BubR1 binding. , 2009, Developmental cell.

[10]  A. Fry,et al.  Under arrest in mitosis: Cdc20 dies twice , 2008, Nature Cell Biology.

[11]  D. Cimini.  Merotelic kinetochore orientation, aneuploidy, and cancer. , 2008, Biochimica et biophysica acta.

[12]  Viji M. Draviam,et al.  Studying chromosome instability in the mouse. , 2008, Biochimica et biophysica acta.

[13]  D. Pellman,et al.  Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes. , 2008, Genes & development.

[14]  Stephen S. Taylor,et al.  Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. , 2008, Cancer cell.

[15]  Yusuke Nakamura,et al.  Detection of novel cancer‐testis antigen‐specific T‐cell responses in TIL, regional lymph nodes, and PBL in patients with esophageal squamous cell carcinoma , 2008, Cancer science.

[16]  Stephen S. Taylor,et al.  Mps1 kinase activity restrains anaphase during an unperturbed mitosis and targets Mad2 to kinetochores , 2008, The Journal of cell biology.

[17]  J. Loncarek,et al.  Extra centrosomes and/or chromosomes prolong mitosis in human cells , 2008, Nature Cell Biology.

[18]  G. Kops.  The kinetochore and spindle checkpoint in mammals. , 2008, Frontiers in bioscience : a journal and virtual library.

[19]  H. Satzinger.  Theodor and Marcella Boveri: chromosomes and cytoplasm in heredity and development , 2008, Nature Reviews Genetics.

[20]  S. Wacholder,et al.  Gene Expression Signature of Cigarette Smoking and Its Role in Lung Adenocarcinoma Development and Survival , 2008, PloS one.

[21]  F. Bertucci,et al.  Sixteen-kinase gene expression identifies luminal breast cancers with poor prognosis. , 2008, Cancer research.

[22]  R. Medema,et al.  Mps1 Phosphorylates Borealin to Control Aurora B Activity and Chromosome Alignment , 2008, Cell.

[23]  Yingming Zhao,et al.  Autophosphorylation-dependent activation of human Mps1 is required for the spindle checkpoint , 2007, Proceedings of the National Academy of Sciences.

[24]  M. Bittner,et al.  A cell proliferation and chromosomal instability signature in anaplastic thyroid carcinoma. , 2007, Cancer research.

[25]  E. Salmon,et al.  The spindle-assembly checkpoint in space and time , 2007, Nature Reviews Molecular Cell Biology.

[26]  M. Malumbres,et al.  Targeting cell cycle kinases for cancer therapy. , 2007, Current medicinal chemistry.

[27]  Jeffrey R. Jackson,et al.  Targeted anti-mitotic therapies: can we improve on tubulin agents? , 2007, Nature Reviews Cancer.

[28]  S. Jablonski,et al.  Mapping the assembly pathways that specify formation of the trilaminar kinetochore plates in human cells , 2006, The Journal of cell biology.

[29]  Kendra S. Burbank,et al.  Genome-wide genetic analysis of polyploidy in yeast , 2006, Nature.

[30]  R. Shoemaker.  The NCI60 human tumour cell line anticancer drug screen , 2006, Nature Reviews Cancer.

[31]  J. Peters.  The anaphase promoting complex/cyclosome: a machine designed to destroy , 2006, Nature Reviews Molecular Cell Biology.

[32]  Z. Szallasi,et al.  A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers , 2006, Nature Genetics.

[33]  Ju-Hyung Woo,et al.  Increased Expression of Mitotic Checkpoint Genes in Breast Cancer Cells with Chromosomal Instability , 2006, Clinical Cancer Research.

[34]  Marc Schmidt,et al.  Ablation of the spindle assembly checkpoint by a compound targeting Mps1 , 2005, EMBO reports.

[35]  Geert J P L Kops,et al.  Lethality to human cancer cells through massive chromosome loss by inhibition of the mitotic checkpoint. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[36]  J. Weinstein,et al.  Karyotypic complexity of the NCI-60 drug-screening panel. , 2003, Cancer research.

[37]  Stephen L. Johnson,et al.  Mps1 defines a proximal blastemal proliferative compartment essential for zebrafish fin regeneration. , 2002, Development.

[38]  Lionel Arnaud,et al.  Human Mps1 kinase is required for the spindle assembly checkpoint but not for centrosome duplication , 2002, The EMBO journal.

[39]  Stephen S. Taylor,et al.  Aneuploid colon cancer cells have a robust spindle checkpoint , 2001, EMBO reports.

[40]  M. Kruhøffer,et al.  Identification of gene expression patterns in superficial and invasive human bladder cancer. , 2001, Cancer research.

[41]  K. Kinzler,et al.  Characterization of MAD2B and other mitotic spindle checkpoint genes. , 1999, Genomics.

[42]  Eric L. Weiss,et al.  The Saccharomyces cerevisiae spindle pole body duplication gene MPS1 is part of a mitotic checkpoint , 1996, The Journal of cell biology.

[43]  M. Winey,et al.  MPS1 and MPS2: novel yeast genes defining distinct steps of spindle pole body duplication , 1991, The Journal of cell biology.

[44]  P. Eyers,et al.  Phosphoregulation of human Mps1 kinase. , 2009, The Biochemical journal.

[45]  Y. Miyagi,et al.  Overexpression of the mitotic spindle assembly checkpoint genes hBUB1, hBUBR1 and hMAD2 in thyroid carcinomas with aggressive nature. , 2008, Anticancer research.

[46]  Cristina Montagna,et al.  Aneuploidy acts both oncogenically and as a tumor suppressor. , 2007, Cancer cell.

[47]  S. Lowe,et al.  Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. , 2007, Cancer cell.

[48]  青木 悠里.  Label-free kinase profiling using phosphate-affinity polyacrylamide gel electrophoresis , 2007 .

[49]  D. Hogg,et al.  Cell cycle dependent regulation of the protein kinase TTK. , 1994, Oncogene.