A High-Throughput Screen to Identify LRRK2 Kinase Inhibitors for the Treatment of Parkinson's Disease Using RapidFire Mass Spectrometry
LRRK2 is a large multidomain protein containing two functional enzymatic domains: a GTPase domain and a protein kinase domain. Dominant coding mutations in the LRRK2 protein are associated with Parkinson's disease (PD). Among such pathogenic mutations, Gly2019Ser mutation in the LRRK2 kinase do...
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Published in | Journal of biomolecular screening Vol. 21; no. 2; pp. 145 - 155 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
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01.02.2016
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Abstract | LRRK2 is a large multidomain protein containing two functional enzymatic domains: a GTPase domain and a protein kinase domain. Dominant coding mutations in the LRRK2 protein are associated with Parkinson's disease (PD). Among such pathogenic mutations, Gly2019Ser mutation in the LRRK2 kinase domain is the most frequent cause of familial PD in Caucasians and is also found in some apparently sporadic PD cases. This mutation results in 2- to 3-fold elevated LRRK2 kinase activity compared with wild type, providing a clear clinical hypothesis for the application of kinase inhibitors in the treatment of this disease. To date, reported screening assays for LRRK2 have been based on detection of labeled adenosine triphosphate and adenosine diphosphate or on antibody-based detection of phosphorylation events. While these assays do offer a high-throughput method of monitoring LRRK2 kinase activity, they are prone to interference from autofluorescent compounds and nonspecific events. Here we describe a label-free assay for LRRK2 kinase activity using the RapidFire mass spectrometry system. This assay format was found to be highly robust and enabled a screen of 100,000 lead-like small molecules. The assay successfully identified a number of known LRRK2 chemotypes that met stringent physicochemical criteria. |
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AbstractList | LRRK2 is a large multidomain protein containing two functional enzymatic domains: a GTPase domain and a protein kinase domain. Dominant coding mutations in the LRRK2 protein are associated with Parkinson's disease (PD). Among such pathogenic mutations, Gly2019Ser mutation in the LRRK2 kinase domain is the most frequent cause of familial PD in Caucasians and is also found in some apparently sporadic PD cases. This mutation results in 2- to 3-fold elevated LRRK2 kinase activity compared with wild type, providing a clear clinical hypothesis for the application of kinase inhibitors in the treatment of this disease. To date, reported screening assays for LRRK2 have been based on detection of labeled adenosine triphosphate and adenosine diphosphate or on antibody-based detection of phosphorylation events. While these assays do offer a high-throughput method of monitoring LRRK2 kinase activity, they are prone to interference from autofluorescent compounds and nonspecific events. Here we describe a label-free assay for LRRK2 kinase activity using the RapidFire mass spectrometry system. This assay format was found to be highly robust and enabled a screen of 100,000 lead-like small molecules. The assay successfully identified a number of known LRRK2 chemotypes that met stringent physicochemical criteria. |
Author | Leveridge, Melanie Edge, Colin Leavens, Bill Collier, Lee Hardwicke, Phil Ratcliffe, Steve Rees, Mike Stasi, Luigi Piero Nadin, Alan Reith, Alastair D |
Author_xml | – sequence: 1 givenname: Melanie surname: Leveridge fullname: Leveridge, Melanie email: melanie.v.leveridge@gsk.com organization: Department of Platform Technology and Science, GlaxoSmithKline Pharmaceuticals R&D, Hertfordshire, UK melanie.v.leveridge@gsk.com – sequence: 2 givenname: Lee surname: Collier fullname: Collier, Lee organization: Department of Platform Technology and Science, GlaxoSmithKline Pharmaceuticals R&D, Hertfordshire, UK Cancer Research Technology, Babraham Research Campus, Cambridge, UK – sequence: 3 givenname: Colin surname: Edge fullname: Edge, Colin organization: Department of Platform Technology and Science, GlaxoSmithKline Pharmaceuticals R&D, Hertfordshire, UK – sequence: 4 givenname: Phil surname: Hardwicke fullname: Hardwicke, Phil organization: Department of Platform Technology and Science, GlaxoSmithKline Pharmaceuticals R&D, Hertfordshire, UK – sequence: 5 givenname: Bill surname: Leavens fullname: Leavens, Bill organization: Department of Platform Technology and Science, GlaxoSmithKline Pharmaceuticals R&D, Hertfordshire, UK – sequence: 6 givenname: Steve surname: Ratcliffe fullname: Ratcliffe, Steve organization: Department of Platform Technology and Science, GlaxoSmithKline Pharmaceuticals R&D, Hertfordshire, UK – sequence: 7 givenname: Mike surname: Rees fullname: Rees, Mike organization: Department of Platform Technology and Science, GlaxoSmithKline Pharmaceuticals R&D, Hertfordshire, UK – sequence: 8 givenname: Luigi Piero surname: Stasi fullname: Stasi, Luigi Piero organization: Neurodegeneration DPU, Neurosciences Therapy Area Unit, GlaxoSmithKline, Pharmaceuticals R&D, Hertfordshire, UK, and Pudong, China Nuevolution A/S, Rønnegade 8, DK-2100 Copenhagen, Denmark – sequence: 9 givenname: Alan surname: Nadin fullname: Nadin, Alan organization: Department of Platform Technology and Science, GlaxoSmithKline Pharmaceuticals R&D, Hertfordshire, UK – sequence: 10 givenname: Alastair D surname: Reith fullname: Reith, Alastair D organization: Neurodegeneration DPU, Neurosciences Therapy Area Unit, GlaxoSmithKline, Pharmaceuticals R&D, Hertfordshire, UK, and Pudong, China |
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Keywords | LRRKtide mass spectrometry RapidFire LRRK2 Parkinson’s disease |
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SubjectTerms | Animals Cell Line DNA, Complementary - genetics GTP Phosphohydrolases - metabolism High-Throughput Screening Assays - methods Humans Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Mass Spectrometry - methods Mutation - genetics Parkinson Disease - drug therapy Phosphorylation - genetics Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Protein Structure, Tertiary - genetics Protein-Serine-Threonine Kinases - antagonists & inhibitors Sf9 Cells |
Title | A High-Throughput Screen to Identify LRRK2 Kinase Inhibitors for the Treatment of Parkinson's Disease Using RapidFire Mass Spectrometry |
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