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

被引：187

作者：

Kwiatkowski, Nicholas ^{[1
,2
]}

Jelluma, Nannette ^{[3
,4
]}

Filippakopoulos, Panagis ^{[5
,6
]}

Soundararajan, Meera ^{[5
,6
]}

Manak, Michael S. ^{[7
]}

Kwon, Mijung ^{[8
]}

Choi, Hwan Geun ^{[1
,2
]}

Sim, Taebo ^{[1
,2
]}

Deveraux, Quinn L. ^{[9
]}

Rottmann, Sabine ^{[9
]}

Pellman, David ^{[8
]}

Shah, Jagesh V. ^{[7
]}

Kops, Geert J. P. L. ^{[3
,4
]}

Knapp, Stefan ^{[5
,6
]}

Gray, Nathanael S. ^{[1
,2
]}

机构：

[1] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[3] Univ Med Ctr Utrecht, Dept Physiol Chem, Utrecht, Netherlands

[4] Univ Med Ctr Utrecht, Canc Genom Ctr, Utrecht, Netherlands

[5] Univ Oxford, Struct Genom Consortium, Oxford, England

[6] Univ Oxford, Dept Clin Pharmacol, Oxford, England

[7] Brigham & Womens Hosp, Div Renal, Harvard Inst Med, Boston, MA 02115 USA

[8] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[9] Novartis Res Fdn, Genom Inst, San Diego, CA USA

来源：

NATURE CHEMICAL BIOLOGY | 2010年 / 6卷 / 05期

基金：

英国惠康基金;

关键词：

SPINDLE-ASSEMBLY CHECKPOINT; POLE BODY DUPLICATION; RECEPTOR TYROSINE KINASE; GROWTH IN-VIVO; MITOTIC CHECKPOINT; CENTROSOME DUPLICATION; KINETOCHORE LOCALIZATION; CHROMOSOMAL INSTABILITY; EXTRA CENTROSOMES; PROTEIN-KINASE;

D O I：

10.1038/nchembio.345

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：359 / 368

页数：10

共 50 条

[11] A small molecule-kinase interaction map for clinical kinase inhibitors [J].

Fabian, MA ;

Biggs, WH ;

Treiber, DK ;

Atteridge, CE ;

Azimioara, MD ;

Benedetti, MG ;

Carter, TA ;

Ciceri, P ;

Edeen, PT ;

Floyd, M ;

Ford, JM ;

Galvin, M ;

Gerlach, JL ;

Grotzfeld, RM ;

Herrgard, S ;

Insko, DE ;

Insko, MA ;

Lai, AG ;

Lélias, JM ;

Mehta, SA ;

Milanov, ZV ;

Velasco, AM ;

Wodicka, LM ;

Patel, HK ;

Zarrinkar, PP ;

Lockhart, DJ .

NATURE BIOTECHNOLOGY, 2005, 23 (03) :329-336

[12] Human Mps1 protein kinase is required for centrosome duplication and normal mitotic progression [J].

Fisk, HA ;

Mattison, CP ;

Winey, M .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (25) :14875-14880

[13] The mouse Mps1p-like kinase regulates centrosome duplication [J].

Fisk, HA ;

Winey, M .

CELL, 2001, 106 (01) :95-104

[14] Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK [J].

Galkin, Anna V. ;

Melnick, Jonathan S. ;

Kim, Sungjoon ;

Hood, Tami L. ;

Li, Nanxin ;

Li, Lintong ;

Xia, Gang ;

Steensma, Ruo ;

Chopiuk, Greg ;

Jiang, Jiqing ;

Wan, Yongqin ;

Ding, Peter ;

Liu, Yi ;

Sun, Fangxian ;

Schultz, Peter G. ;

Gray, Nathanael S. ;

Warmuth, Markus .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (01) :270-275

[15] VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo [J].

Harrington, EA ;

Bebbington, D ;

Moore, J ;

Rasmussen, RK ;

Ajose-Adeogun, AO ;

Nakayama, T ;

Graham, JA ;

Demur, C ;

Hercend, T ;

Diu-Hercend, A ;

Su, M ;

Golec, JMC ;

Miller, KM .

NATURE MEDICINE, 2004, 10 (03) :262-267

[16] Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis [J].

Holland, Andrew J. ;

Cleveland, Don W. .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2009, 10 (07) :478-487

[17] Spindle checkpoint protein dynamics at kinetochores in living cells [J].

Howell, BJ ;

Moree, B ;

Farrar, EM ;

Stewart, S ;

Fang, GW ;

Salmon, ED .

CURRENT BIOLOGY, 2004, 14 (11) :953-964

[18] Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system [J].

Iwahara, T ;

Fujimoto, J ;

Wen, DZ ;

Cupples, R ;

Bucay, N ;

Arakawa, T ;

Mori, S ;

Ratzkin, B ;

Yamamoto, T .

ONCOGENE, 1997, 14 (04) :439-449

[19] Elevating the frequency of chromosome mis-segregation as a strategy to kill tumor cells [J].

Janssen, Aniek ;

Kops, Geert J. P. L. ;

Medema, Rene H. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (45) :19108-19113

[20] Mps1 phosphorylates borealin to control aurora B activity and chromosome alignment [J].

Jelluma, Nannette ;

Brenkman, Arjan B. ;

van den Broek, Niels J. F. ;

Cruijsen, Carin W. A. ;

van Osch, Maria H. J. ;

Lens, Susanne M. A. ;

Medema, Rene H. ;

Kops, Geert J. P. L. .

CELL, 2008, 132 (02) :233-246

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