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PMID: 20383151 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Small-molecule kinase inhibitors provide insight into Mps1 cell cycle function.

Nature chemical biology ·Vol. 6 ·No. 5 ·2010-05-00 ·Pages 359-68

Kwiatkowski N, Jelluma N, Filippakopoulos P, Soundararajan M, Manak MS, Kwon M, Choi HG, Sim T, Deveraux QL, Rottmann S, Pellman D, Shah JV, Kops GJ, Knapp S, Gray NS

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.

MeSH Terms
Cell Cycle Cell Cycle Proteins/physiology Enzyme Inhibitors/pharmacology Models, Molecular Protein Kinase Inhibitors/chemistry,pharmacology Protein Serine-Threonine Kinases/physiology Protein-Tyrosine Kinases
Chemicals
Cell Cycle Proteins Enzyme Inhibitors Protein Kinase Inhibitors Protein-Tyrosine Kinases Protein Serine-Threonine Kinases TTK protein, human
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Kwiatkowski Nicholas
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Jelluma Nannette
Filippakopoulos Panagis
Soundararajan Meera
Manak Michael S
Kwon Mijung
Choi Hwan Geun
Sim Taebo
Deveraux Quinn L
Rottmann Sabine
Pellman David
Shah Jagesh V
Kops Geert J P L
Knapp Stefan
Gray Nathanael S
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Article Info
Journal
Nature chemical biology
Abbr.
Nat Chem Biol
ISSN
1552-4469
DOI
10.1038/nchembio.345
Published
2010-05-00
Epub
2010-00-11
Pages
359-68
Language
English
Region
United States
NLM ID
101231976
PMCID
PMC2857554
Subset
IM
Grants
Wellcome Trust · United Kingdom
CIHR · Canada
NIGMS NIH HHS · R01 GM077238-04 · United States
NIGMS NIH HHS · P41 GM079575-03 · United States
NIGMS NIH HHS · P41 GM079575 · United States
NIGMS NIH HHS · R01 GM077238-03 · United States
NIGMS NIH HHS · R01 GM077238 · United States
Databases
PubChem-Substance
90945060, 90945061, 90945062
External Links
PubMed source DOI: 10.1038/nchembio.345 PMC Full Text View journal details
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