title: Targeting the mitotic checkpoint for cancer therapy with NMS-P715, an inhibitor of MPS1 kinase.
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.
authors.affiliation: Department of Cell Biology-Oncology, Nerviano Medical Sciences, Viale Pasteur 10, Nerviano 20014, Italy. riccardo.colombo@nervianoms.com
authors.forename: Riccardo
authors.initials: R
authors.lastname: Colombo
authors.forename: Marina
authors.initials: M
authors.lastname: Caldarelli
authors.forename: Milena
authors.initials: M
authors.lastname: Mennecozzi
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Giorgini
authors.forename: Francesco
authors.initials: F
authors.lastname: Sola
authors.forename: Paolo
authors.initials: P
authors.lastname: Cappella
authors.forename: Claudia
authors.initials: C
authors.lastname: Perrera
authors.forename: Stefania Re
authors.initials: SR
authors.lastname: Depaolini
authors.forename: Luisa
authors.initials: L
authors.lastname: Rusconi
authors.forename: Ulisse
authors.initials: U
authors.lastname: Cucchi
authors.forename: Nilla
authors.initials: N
authors.lastname: Avanzi
authors.forename: Jay Aaron
authors.initials: JA
authors.lastname: Bertrand
authors.forename: Roberto Tiberio
authors.initials: RT
authors.lastname: Bossi
authors.forename: Enrico
authors.initials: E
authors.lastname: Pesenti
authors.forename: Arturo
authors.initials: A
authors.lastname: Galvani
authors.forename: Antonella
authors.initials: A
authors.lastname: Isacchi
authors.forename: Francesco
authors.initials: F
authors.lastname: Colotta
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.forename: Jürgen
authors.initials: J
authors.lastname: Moll
mesh_terms: D000782:Aneuploidy; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D048708:Cell Growth Processes / Q000187:drug effects; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects*; D008958:Models, Molecular; D058990:Molecular Targeted Therapy / Q000379:methods; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011505:Protein-Tyrosine Kinases; D011720:Pyrazoles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D008941:Spindle Apparatus / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C555141:N-(2,6-diethylphenyl)-1-methyl-8-((4-((1-methylpiperidin-4-yl)carbamoyl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo(4,3-h)quinazoline-3-carboxamide; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011799:Quinazolines; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human