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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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.).
M.P.P. and T.K.N. are employees of ActivX Biosciences.
Supplementary Methods, Supplementary Schemes 1 & 2, Supplementary Tables 1 & 2 and Supplementary Figures 1–12 (PDF 4952 kb)
Live cell film of LRRK2[G2019S] treated with LRRK2-IN-1 (MOV 11685 kb)
Live cell film of LRRK2[wt] treated with LRRK2-IN-1 (MOV 9303 kb)
Live cell film of LRRK2[A2016T] treated with LRRK2-IN-1 (MOV 4783 kb)
Live cell film of LRRK2[A2016T+G2019S] treated with LRRK2-IN-1 (MOV 11945 kb)
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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