Brain penetrant LRRK2 inhibitor

Hwan Geun Choi; Jinwei Zhang; Xianming Deng; John M. Hatcher; Matthew P. Patricelli; Zheng Zhao; Dario R. Alessi; Nathanael S. Gray

doi:10.1021/ml300123a

Brain penetrant LRRK2 inhibitor

Hwan Geun Choi, Jinwei Zhang, Xianming Deng, John M. Hatcher, Matthew P. Patricelli, Zheng Zhao, Dario R. Alessi, Nathanael S. Gray

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

115 Citations (Scopus)

Abstract

Activating mutations in leucine-rich repeat kinase 2 (LARK2) are present in a subset of Parkinson's disease (PD) patients and may represent an attractive therapeutic target. Here, we report that a 2-anilino-4-methylamino-5-chloropyrimidine, HG-10-102-01 (4), is a potent and selective inhibitor of wild-type LRRK2 and the G2019S mutant. Compound 4 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3 mu M in cells and is the first compound reported to be capable of inhibiting Ser910 and Ser935 phosphorylation in mouse brain following intraperitoneal delivery of doses as low as 50 mg/kg.

Original language	English
Pages (from-to)	658-662
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	3
Issue number	8
DOIs	https://doi.org/10.1021/ml300123a
Publication status	Published - 9 Aug 2012

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10.1021/ml300123a

A Systematic Investigation into the Pathogenesis and Course of Parkinson's Syndrome (Wellcome Trust and MRC Neurodegenerative Diseases Initiative) (Joint with University College London)
Alessi, D. (Investigator)
Medical Research Council
1/09/10 → 31/08/15
Project: Research

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title = "Brain penetrant LRRK2 inhibitor",

abstract = "Activating mutations in leucine-rich repeat kinase 2 (LARK2) are present in a subset of Parkinson's disease (PD) patients and may represent an attractive therapeutic target. Here, we report that a 2-anilino-4-methylamino-5-chloropyrimidine, HG-10-102-01 (4), is a potent and selective inhibitor of wild-type LRRK2 and the G2019S mutant. Compound 4 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3 mu M in cells and is the first compound reported to be capable of inhibiting Ser910 and Ser935 phosphorylation in mouse brain following intraperitoneal delivery of doses as low as 50 mg/kg.",

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T1 - Brain penetrant LRRK2 inhibitor

AU - Choi, Hwan Geun

AU - Zhang, Jinwei

AU - Deng, Xianming

AU - Hatcher, John M.

AU - Patricelli, Matthew P.

AU - Zhao, Zheng

AU - Alessi, Dario R.

AU - Gray, Nathanael S.

PY - 2012/8/9

Y1 - 2012/8/9

N2 - Activating mutations in leucine-rich repeat kinase 2 (LARK2) are present in a subset of Parkinson's disease (PD) patients and may represent an attractive therapeutic target. Here, we report that a 2-anilino-4-methylamino-5-chloropyrimidine, HG-10-102-01 (4), is a potent and selective inhibitor of wild-type LRRK2 and the G2019S mutant. Compound 4 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3 mu M in cells and is the first compound reported to be capable of inhibiting Ser910 and Ser935 phosphorylation in mouse brain following intraperitoneal delivery of doses as low as 50 mg/kg.

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DO - 10.1021/ml300123a

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JO - ACS Medicinal Chemistry Letters

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Brain penetrant LRRK2 inhibitor

Abstract

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Projects

A Systematic Investigation into the Pathogenesis and Course of Parkinson's Syndrome (Wellcome Trust and MRC Neurodegenerative Diseases Initiative) (Joint with University College London)

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