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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Benzodiazepinones / pharmacology*
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Dose-Response Relationship, Drug
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Enzyme Activation
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Enzyme Inhibitors / pharmacology*
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HEK293 Cells
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Humans
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Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
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Mutation
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Parkinson Disease / genetics
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Parkinson Disease / metabolism*
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Parkinson Disease / pathology
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Phosphorylation
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / chemistry
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Pyrimidines / pharmacology*
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Serine / chemistry
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Serine / metabolism
Substances
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Benzodiazepinones
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Enzyme Inhibitors
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LRRK2-IN1
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Pyrimidines
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Serine
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LRRK2 protein, human
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Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
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Protein Serine-Threonine Kinases
Associated data
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PubChem-Substance/104548353
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PubChem-Substance/104548354
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PubChem-Substance/104548355
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PubChem-Substance/104548356
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PubChem-Substance/104548357