title: Small-molecule kinase inhibitors provide insight into Mps1 cell cycle function.
abstract: Mps1, a dual-specificity kinase, is required for the proper functioning of the spindle assembly checkpoint and for the maintenance of chromosomal stability. As Mps1 function has been implicated in numerous phases of the cell cycle, the development of a potent, selective small-molecule inhibitor of Mps1 should facilitate dissection of Mps1-related biology. We describe the cellular effects and Mps1 cocrystal structures of new, selective small-molecule inhibitors of Mps1. Consistent with RNAi studies, chemical inhibition of Mps1 leads to defects in Mad1 and Mad2 establishment at unattached kinetochores, decreased Aurora B kinase activity, premature mitotic exit and gross aneuploidy, without any evidence of centrosome duplication defects. However, in U2OS cells having extra centrosomes (an abnormality found in some cancers), Mps1 inhibition increases the frequency of multipolar mitoses. Lastly, Mps1 inhibitor treatment resulted in a decrease in cancer cell viability.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kwiatkowski
authors.forename: Nannette
authors.initials: N
authors.lastname: Jelluma
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.forename: Meera
authors.initials: M
authors.lastname: Soundararajan
authors.forename: Michael S
authors.initials: MS
authors.lastname: Manak
authors.forename: Mijung
authors.initials: M
authors.lastname: Kwon
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.forename: Quinn L
authors.initials: QL
authors.lastname: Deveraux
authors.forename: Sabine
authors.initials: S
authors.lastname: Rottmann
authors.forename: David
authors.initials: D
authors.lastname: Pellman
authors.forename: Jagesh V
authors.initials: JV
authors.lastname: Shah
authors.forename: Geert J P L
authors.initials: GJ
authors.lastname: Kops
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011505:Protein-Tyrosine Kinases
chemical_list: D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human
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