Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2

Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) are strongly associated with late-onset autosomal dominant Parkinson's disease. We employed a new, parallel, compound-centric approach to identify a potent and selective LRRK2 inhibitor, LRRK2-IN-1, and demonstrated that inhibition of LRRK2 induces dephosphorylation of Ser910 and Ser935 and accumulation of LRRK2 within aggregate structures. LRRK2-IN-1 will serve as a versatile tool to pharmacologically interrogate LRRK2 biology and study its role in Parkinson's disease.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Enzymatic activity of LRRK2-IN-1 and its selectivity.
Figure 2: LRRK2-IN-1 inhibits LRRK2 in vivo.
Figure 3: LRRK2-IN-1 alters the cytoplasmic localization of LRRK2.

References

  1. Gandhi, P.N., Chen, S.G. & Wilson-Delfosse, A.L. J. Neurosci. Res. 87, 1283–1295 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Zimprich, A. et al. Neuron 44, 601–607 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Paisán-Ruíz, C. et al. Neuron 44, 595–600 (2004).

    Article  PubMed  Google Scholar 

  4. Healy, D.G. et al. Lancet Neurol. 7, 583–590 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Dächsel, J.C. & Farrer, M.J. Arch. Neurol. 67, 542–547 (2010).

    Article  PubMed  Google Scholar 

  6. Greggio, E. & Cookson, M.R. ASN Neuro 1, e00002 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Covy, J.P. & Giasson, B.I. Biochem. Biophys. Res. Commun. 378, 473–477 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Anand, V.S. et al. FEBS J. 276, 466–478 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Nichols, R.J. et al. Biochem. J. 424, 47–60 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Lee, B.D. et al. Nat. Med. 16, 998–1000 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Goldstein, D.M., Gray, N.S. & Zarrinkar, P.P. Nat. Rev. Drug Discov. 7, 391–397 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Fabian, M.A. et al. Nat. Biotechnol. 23, 329–336 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Karaman, M.W. et al. Nat. Biotechnol. 26, 127–132 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Bain, J. et al. Biochem. J. 408, 297–315 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Patricelli, M.P. et al. Biochemistry 46, 350–358 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Nichols, R.J. et al. Biochem. J. 430, 393–404 (2010).

    Article  CAS  PubMed  Google Scholar 

  17. Dzamko, N. et al. Biochem. J. 430, 405–413 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Alegre-Abarrategui, J. et al. Hum. Mol. Genet. 18, 4022–4034 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Greggio, E. et al. Neurobiol. Dis. 23, 329–341 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Alessi, D.R. et al. J. Biol. Chem. 270, 27489–27494 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Cuenda, A. et al. FEBS Lett. 364, 229–233 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Vlahos, C.J. et al. J. Biol. Chem. 269, 5241–5248 (1994).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We wish to thank staff at the National Centre for Protein Kinase Profiling (http://www.kinase-screen.mrc.ac.uk) for undertaking Dundee kinase specificity screening, F. Hentati (Institut National de Neurologie, Tunisia) and A. Reith (GlaxoSmithKline Pharmaceuticals Research and Development) for providing EBV immortalized human lymphoblastoid cells, P. Bamborough (GlaxoSmithKline Pharmaceuticals Research and Development) for providing LRRK2 homology model and the antibody purification teams (Division of Signal Transduction Therapy (DSTT), University of Dundee) coordinated by H. McLauchlan and J. Hastie for generation of antibodies. This work was supported by US National Institutes of Health grant P41 GM079575-03 (N.S.G.), the Medical Research Council Technology Industry Collaboration Award and a National Health and Medical Research Council postdoctoral fellowship (N.D.), the Medical Research Council (D.R.A.), the Michael J. Fox Foundation for Parkinson's Disease Research (D.R.A.), the pharmaceutical companies supporting the DSTT (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck KgaA and Pfizer) (D.R.A.), the US National Institutes of Health grants CA079871 and CA114059 (J.-D.L.) and funds from the Tobacco-Related Disease Research Program of the University of California, 19XT-0084, (J.-D.L.).

Author information

Authors and Affiliations

Authors

Contributions

N.S.G. conceived and directed the chemistry effort. X.D. performed the chemical synthesis and structure-activity relationship analysis. D.R.A. conceived and directed the biology effort. N.D. performed the biology experimental research with assistance from A.P. (confocal microscopy and live cell imaging). P.D. performed the SHSY5Y experiment. Q.L. performed the modeling study. Q.Y. and J.-D.L. performed the MAPK7 cellular assay. M.P.P. and T.K.N. performed the KiNativ selectivity profiling and data analysis. X.D., N.D., D.R.A. and N.S.G. co-wrote the paper. All authors read and edited the manuscript.

Corresponding authors

Correspondence to Dario R Alessi or Nathanael S Gray.

Ethics declarations

Competing interests

M.P.P. and T.K.N. are employees of ActivX Biosciences.

Supplementary information

Supplementary Text and Figures

Supplementary Methods, Supplementary Schemes 1 & 2, Supplementary Tables 1 & 2 and Supplementary Figures 1–12 (PDF 4952 kb)

Supplementary Movie 1

Live cell film of LRRK2[G2019S] treated with LRRK2-IN-1 (MOV 11685 kb)

Supplementary Movie 2

Live cell film of LRRK2[wt] treated with LRRK2-IN-1 (MOV 9303 kb)

Supplementary Movie 3

Live cell film of LRRK2[A2016T] treated with LRRK2-IN-1 (MOV 4783 kb)

Supplementary Movie 4

Live cell film of LRRK2[A2016T+G2019S] treated with LRRK2-IN-1 (MOV 11945 kb)

Supplementary Data Set

Chemical probe LRRK2-IN-1 (XLS 205 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Deng, X., Dzamko, N., Prescott, A. et al. Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2. Nat Chem Biol 7, 203–205 (2011). https://doi.org/10.1038/nchembio.538

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.538

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research