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

Xianming Deng; Nicolas Dzamko; Alan Prescott; Paul Davies; Qingsong Liu; Qingkai Yang; Jiing-Dwan Lee; Matthew P. Patricelli; Tyzoon K. Nomanbhoy; Dario R. Alessi; Nathanael S. Gray

doi:10.1038/NCHEMBIO.538

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

Xianming Deng, Nicolas Dzamko, Alan Prescott, Paul Davies, Qingsong Liu, Qingkai Yang, Jiing-Dwan Lee, Matthew P. Patricelli, Tyzoon K. Nomanbhoy, Dario R. Alessi, Nathanael S. Gray

Research output: Contribution to journal › Article › peer-review

352 Citations (Scopus)

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.

Original language	English
Pages (from-to)	203-205
Number of pages	3
Journal	Nature Chemical Biology
Volume	7
Issue number	4
DOIs	https://doi.org/10.1038/NCHEMBIO.538
Publication status	Published - Apr 2011

Keywords

CYTOPLASMIC LOCALIZATION
14-3-3 BINDING
MUTATIONS
MAP

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title = "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.",

keywords = "CYTOPLASMIC LOCALIZATION, 14-3-3 BINDING, MUTATIONS, MAP",

author = "Xianming Deng and Nicolas Dzamko and Alan Prescott and Paul Davies and Qingsong Liu and Qingkai Yang and Jiing-Dwan Lee and Patricelli, {Matthew P.} and Nomanbhoy, {Tyzoon K.} and Alessi, {Dario R.} and Gray, {Nathanael S.}",

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doi = "10.1038/NCHEMBIO.538",

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journal = "Nature Chemical Biology",

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T1 - Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2

AU - Deng, Xianming

AU - Dzamko, Nicolas

AU - Prescott, Alan

AU - Davies, Paul

AU - Liu, Qingsong

AU - Yang, Qingkai

AU - Lee, Jiing-Dwan

AU - Patricelli, Matthew P.

AU - Nomanbhoy, Tyzoon K.

AU - Alessi, Dario R.

AU - Gray, Nathanael S.

PY - 2011/4

Y1 - 2011/4

N2 - 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.

AB - 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.

KW - CYTOPLASMIC LOCALIZATION

KW - 14-3-3 BINDING

KW - MUTATIONS

KW - MAP

U2 - 10.1038/NCHEMBIO.538

DO - 10.1038/NCHEMBIO.538

M3 - Article

SN - 1552-4450

VL - 7

SP - 203

EP - 205

JO - Nature Chemical Biology

JF - Nature Chemical Biology

IS - 4

ER -

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

Abstract

Keywords

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