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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.

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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.

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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.).

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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.

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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)

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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

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