Small Molecule Kinase Inhibitors Provide Insight into Mps1 Cell Cycle Function View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2010-04-11

AUTHORS

Nicholas Kwiatkowski, Nannette Jelluma, Panagis Filippakopoulos, Meera Soundararajan, Michael S. Manak, Mijung Kwon, Hwan Geun Choi, Taebo Sim, Quinn L. Deveraux, Sabine Rottmann, David Pellman, Jagesh V. Shah, Geert J.P.L. Kops, Stefan Knapp, Nathanael S. Gray

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. More... »

PAGES

359-368

Journal

TITLE

Nature Chemical Biology

ISSUE

5

VOLUME

6

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nchembio.345

DOI

http://dx.doi.org/10.1038/nchembio.345

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1024590229

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/20383151


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23 schema:description 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.
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30 schema:keywords Aurora B kinase activity
31 B kinase activity
32 MPS1 inhibition
33 Mad1
34 Mad2 establishment
35 Molecule Kinase Inhibitors
36 Mps1
37 Mps1 Cell Cycle Function
38 Mps1 cocrystal structures
39 Mps1 function
40 Mps1 inhibitor treatment
41 RNAi studies
42 U2OS cells
43 activity
44 aneuploidy
45 assembly checkpoint
46 biology
47 cancer cell viability
48 cell cycle
49 cell cycle function
50 cell viability
51 cells
52 cellular effects
53 centrosome duplication defects
54 centrosomes
55 checkpoint
56 chemical inhibition
57 chromosomal stability
58 cocrystal structure
59 cycle
60 cycle function
61 decrease
62 defects
63 development
64 dissection
65 dissection of Mps1
66 dual-specificity kinase
67 duplication defects
68 effect
69 establishment
70 evidence
71 exit
72 extra centrosomes
73 frequency
74 function
75 functioning
76 gross aneuploidy
77 inhibition
78 inhibitor treatment
79 inhibitors
80 insights
81 kinase
82 kinase activity
83 kinase inhibitors
84 kinetochores
85 maintenance
86 mitoses
87 mitotic exit
88 multipolar mitoses
89 numerous phases
90 phase
91 premature mitotic exit
92 proper functioning
93 selective small molecule inhibitors
94 small molecule inhibitors
95 small molecule kinase inhibitors
96 spindle assembly checkpoint
97 stability
98 structure
99 study
100 treatment
101 unattached kinetochores
102 viability
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