title: Characterization of the cellular and antitumor effects of MPI-0479605, a small-molecule inhibitor of the mitotic kinase Mps1.
abstract: Mps1 is a dual specificity protein kinase that is essential for the bipolar attachment of chromosomes to the mitotic spindle and for maintaining the spindle assembly checkpoint until all chromosomes are properly attached. Mps1 is expressed at high levels during mitosis and is abundantly expressed in cancer cells. Disruption of Mps1 function induces aneuploidy and cell death. We report the identification of MPI-0479605, a potent and selective ATP competitive inhibitor of Mps1. Cells treated with MPI-0479605 undergo aberrant mitosis, resulting in aneuploidy and formation of micronuclei. In cells with wild-type p53, this promotes the induction of a postmitotic checkpoint characterized by the ATM- and RAD3-related-dependent activation of the p53-p21 pathway. In both wild-type and p53 mutant cells lines, there is a growth arrest and inhibition of DNA synthesis. Subsequently, cells undergo mitotic catastrophe and/or an apoptotic response. In xenograft models, MPI-0479605 inhibits tumor growth, suggesting that drugs targeting Mps1 may have utility as novel cancer therapeutics.
authors: Myrexis, Inc. Salt Lake City, Utah, USA.
authors: Keith D
authors: KD
authors: Tardif
authors: Aaron
authors: A
authors: Rogers
authors: Jared
authors: J
authors: Cassiano
authors: Bruce L
authors: BL
authors: Roth
authors: Daniel M
authors: DM
authors: Cimbora
authors: Rena
authors: R
authors: McKinnon
authors: Ashley
authors: A
authors: Peterson
authors: Thomas B
authors: TB
authors: Douce
authors: Rosann
authors: R
authors: Robinson
authors: Irene
authors: I
authors: Dorweiler
authors: Thaylon
authors: T
authors: Davis
authors: Mark A
authors: MA
authors: Hess
authors: Kirill
authors: K
authors: Ostanin
authors: Damon I
authors: DI
authors: Papac
authors: Vijay
authors: V
authors: Baichwal
authors: Ian
authors: I
authors: McAlexander
authors: J Adam
authors: JA
authors: Willardsen
authors: Michael
authors: M
authors: Saunders
authors: Hoarau
authors: H
authors: Christophe
authors: D Vijay
authors: DV
authors: Kumar
authors: Daniel A
authors: DA
authors: Wettstein
authors: Robert O
authors: RO
authors: Carlson
authors: Brandi L
authors: BL
authors: Williams
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects / Q000502:physiology; D008954:Models, Biological; D008970:Molecular Weight; D009025:Morpholines / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C571997:MPI-0479605; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; C441620:Ttk protein, mouse; D017346:Protein Serine-Threonine Kinases; D000225:Adenine