Small-molecule kinase inhibitors provide insight into Mps1 cell cycle function.
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.
Kwiatkowski
Nicholas
N
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Jelluma
Nannette
N
Filippakopoulos
Panagis
P
Soundararajan
Meera
M
Manak
Michael S
MS
Kwon
Mijung
M
Choi
Hwan Geun
HG
Sim
Taebo
T
Deveraux
Quinn L
QL
Rottmann
Sabine
S
Pellman
David
D
Shah
Jagesh V
JV
Kops
Geert J P L
GJ
Knapp
Stefan
S
Gray
Nathanael S
NS
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
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human
Nat Biotechnol. 2005 Mar;23(3):329-36
15711537
J Cell Mol Med. 2009 Aug;13(8B):1679-1694
19120698
Biochemistry. 2010 Mar 2;49(8):1689-701
20099905
Dev Cell. 2007 Aug;13(2):190-202
17681131
J Biol Chem. 2008 Aug 1;283(31):21495-500
18480048
Curr Biol. 2004 Jun 8;14(11):942-52
15182667
J Biol Chem. 2004 Mar 26;279(13):12997-3003
14722118
Mol Biol Cell. 2004 Oct;15(10):4584-96
15269280
J Cell Biol. 1991 Aug;114(4):745-54
1869587
Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19936-41
18077425
Cell. 2001 Jul 13;106(1):83-93
11461704
Curr Biol. 2005 Jan 26;15(2):160-5
15668173
Curr Biol. 2007 Feb 20;17(4):316-22
17291758
Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4459-64
15070740
Curr Biol. 2004 Jun 8;14(11):953-64
15182668
Mol Biol Cell. 2009 Jan;20(1):10-20
18923149
Proc Natl Acad Sci U S A. 2009 Nov 10;106(45):19108-13
19855003
Science. 2002 Sep 27;297(5590):2267-70
12351790
Curr Biol. 2005 Jun 7;15(11):1070-6
15936280
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):14875-80
14657364
Mol Biol Cell. 2003 Apr;14(4):1638-51
12686615
Science. 1998 Jan 16;279(5349):349-52
9454332
PLoS One. 2008 Jun 11;3(6):e2415
18545697
Mol Biol Cell. 1998 Apr;9(4):759-74
9529376
Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8699-704
15159543
Drug Resist Updat. 2007 Aug-Oct;10(4-5):162-81
17669681
Oncogene. 1997 Jan 30;14(4):439-49
9053841
Genes Dev. 2008 Aug 15;22(16):2189-203
18662975
Nat Med. 2004 Mar;10(3):262-7
14981513
Cell. 2001 Jul 13;106(1):95-104
11461705
Cancer Res. 2004 Jan 15;64(2):440-5
14744753
Cancer Res. 1990 Sep 15;50(18):6075-86
1975513
EMBO J. 1995 Apr 18;14(8):1655-63
7737118
EMBO J. 1990 Jul;9(7):2279-87
2357970
Nat Rev Mol Cell Biol. 2009 Jul;10(7):478-87
19546858
Nat Biotechnol. 2008 Jan;26(1):127-32
18183025
Chromosoma. 2004 Aug;113(1):1-15
15235793
Nature. 1998 Mar 19;392(6673):300-3
9521327
Cell. 2008 Jan 25;132(2):233-46
18243099
EMBO Rep. 2005 Sep;6(9):866-72
16113653
Nat Cell Biol. 2008 Jun;10(6):748-51
18469805
Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11296-301
16055552
EMBO J. 2002 Apr 2;21(7):1723-32
11927556
J Biol Chem. 2007 Oct 19;282(42):30553-61
17728254
Cell. 2008 Jun 13;133(6):1032-42
18555779
Nature. 2001 Jan 18;409(6818):355-9
11201745
J Cell Biol. 2008 Jun 16;181(6):893-901
18541701
Mol Biol Cell. 2007 Nov;18(11):4457-69
17804818
Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):270-5
17185414
Nat Rev Mol Cell Biol. 2007 May;8(5):379-93
17426725