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

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

doi:10.1038/nchembio.345

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

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

Department of Life Science

Research output: Contribution to journal › Article › peer-review

191 Scopus citations

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.

Original language	English
Pages (from-to)	359-368
Number of pages	10
Journal	Nature Chemical Biology
Volume	6
Issue number	5
DOIs	https://doi.org/10.1038/nchembio.345
State	Published - May 2010

Bibliographical note

Funding Information:
We thank R. King (Harvard Medical School), B. Vogelstein (Howard Hughes Medical Institute and Johns Hopkins Medical Institutions) and E. Nigg (Max Planck Institute of Biochemistry, Munich) for reagents and R. King, T. Mitchison, A. Abrieu, U. Eggert, C. Walsh, F. Sigoillot and E. Chung for helpful discussions. We also thank Ambit Biosciences and Invitrogen Corporation for technical support in the initial compound screening and enzymatic activity assays, respectively, as well as the Nikon Imaging Facility (Harvard Medical School) and the Dana-Farber Flow Cytometry Lab for technical help and instrument use. The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from the Canadian Institutes for Health Research, the Canadian Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck & Co., Inc., the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research and the Wellcome Trust.

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Kwiatkowski, N., Jelluma, N., Filippakopoulos, P., Soundararajan, M., Manak, M. S., Kwon, M., Choi, H. G., Sim, T., Deveraux, Q. L., Rottmann, S., Pellman, D., Shah, J. V., Kops, G. J. P. L., Knapp, S., & Gray, N. S. (2010). Small-molecule kinase inhibitors provide insight into Mps1 cell cycle function. Nature Chemical Biology, 6(5), 359-368. https://doi.org/10.1038/nchembio.345

@article{2670a04f9aa840f395ba22ccacd6b671,

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.",

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

note = "Funding Information: We thank R. King (Harvard Medical School), B. Vogelstein (Howard Hughes Medical Institute and Johns Hopkins Medical Institutions) and E. Nigg (Max Planck Institute of Biochemistry, Munich) for reagents and R. King, T. Mitchison, A. Abrieu, U. Eggert, C. Walsh, F. Sigoillot and E. Chung for helpful discussions. We also thank Ambit Biosciences and Invitrogen Corporation for technical support in the initial compound screening and enzymatic activity assays, respectively, as well as the Nikon Imaging Facility (Harvard Medical School) and the Dana-Farber Flow Cytometry Lab for technical help and instrument use. The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from the Canadian Institutes for Health Research, the Canadian Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck & Co., Inc., the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research and the Wellcome Trust.",

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AU - Jelluma, Nannette

AU - Filippakopoulos, Panagis

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AU - Manak, Michael S.

AU - Kwon, Mijung

AU - Choi, Hwan Geun

AU - Sim, Taebo

AU - Deveraux, Quinn L.

AU - Rottmann, Sabine

AU - Pellman, David

AU - Shah, Jagesh V.

AU - Kops, Geert J.P.L.

AU - Knapp, Stefan

AU - Gray, Nathanael S.

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

Abstract

Bibliographical note

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