Characterization of TAE684 as a potent LRRK2 kinase inhibitor

Jinwei Zhang; Xianming Deng; Hwan Geun Choi; Dario R. Alessi; Nathanael S. Gray

doi:10.1016/j.bmcl.2012.01.084

Characterization of TAE684 as a potent LRRK2 kinase inhibitor

Jinwei Zhang, Xianming Deng, Hwan Geun Choi, Dario R. Alessi (Lead / Corresponding author), Nathanael S. Gray (Lead / Corresponding author)

MRC PPU

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Abstract

Leucine-rich repeat kinase 2 (LRRK2) is linked to Parkinson's disease and may represent an attractive therapeutic target. Here we report a 2,4-dianilino-5-chloro-pyrimidine, TAE684, a previously reported inhibitor of anaplastic lymphoma kinase (ALK), is also a potent inhibitor of LRRK2 kinase activity (IC50 of 7.8 nM against wild-type LRRK2, 6.1 nM against the G2019S mutant). TAE684 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 in mouse spleen and kidney, but not in brain, following oral doses of 10 mg/kg. (c) 2012 Elsevier Ltd. All rights reserved.

Original language	English
Pages (from-to)	1864-1869
Number of pages	6
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	22
Issue number	5
Early online date	28 Jan 2012
DOIs	https://doi.org/10.1016/j.bmcl.2012.01.084
Publication status	Published - 1 Mar 2012

Keywords

Animals
Brain
Cell Line
Cells, Cultured
Humans
Mice
Models, Molecular
Mutation
Parkinson Disease
Protein-Serine-Threonine Kinases
Pyrimidines

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10.1016/j.bmcl.2012.01.084

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.
Medical Research Council, Wellcome Trust
1/09/10 → 31/08/15
Project: Research

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title = "Characterization of TAE684 as a potent LRRK2 kinase inhibitor",

abstract = "Leucine-rich repeat kinase 2 (LRRK2) is linked to Parkinson's disease and may represent an attractive therapeutic target. Here we report a 2,4-dianilino-5-chloro-pyrimidine, TAE684, a previously reported inhibitor of anaplastic lymphoma kinase (ALK), is also a potent inhibitor of LRRK2 kinase activity (IC50 of 7.8 nM against wild-type LRRK2, 6.1 nM against the G2019S mutant). TAE684 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 in mouse spleen and kidney, but not in brain, following oral doses of 10 mg/kg. (c) 2012 Elsevier Ltd. All rights reserved.",

keywords = "Animals, Brain, Cell Line, Cells, Cultured, Humans, Mice, Models, Molecular, Mutation, Parkinson Disease, Protein-Serine-Threonine Kinases, Pyrimidines",

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AU - Zhang, Jinwei

AU - Deng, Xianming

AU - Choi, Hwan Geun

AU - Alessi, Dario R.

AU - Gray, Nathanael S.

PY - 2012/3/1

Y1 - 2012/3/1

N2 - Leucine-rich repeat kinase 2 (LRRK2) is linked to Parkinson's disease and may represent an attractive therapeutic target. Here we report a 2,4-dianilino-5-chloro-pyrimidine, TAE684, a previously reported inhibitor of anaplastic lymphoma kinase (ALK), is also a potent inhibitor of LRRK2 kinase activity (IC50 of 7.8 nM against wild-type LRRK2, 6.1 nM against the G2019S mutant). TAE684 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 in mouse spleen and kidney, but not in brain, following oral doses of 10 mg/kg. (c) 2012 Elsevier Ltd. All rights reserved.

AB - Leucine-rich repeat kinase 2 (LRRK2) is linked to Parkinson's disease and may represent an attractive therapeutic target. Here we report a 2,4-dianilino-5-chloro-pyrimidine, TAE684, a previously reported inhibitor of anaplastic lymphoma kinase (ALK), is also a potent inhibitor of LRRK2 kinase activity (IC50 of 7.8 nM against wild-type LRRK2, 6.1 nM against the G2019S mutant). TAE684 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 in mouse spleen and kidney, but not in brain, following oral doses of 10 mg/kg. (c) 2012 Elsevier Ltd. All rights reserved.

KW - Animals

KW - Brain

KW - Cell Line

KW - Cells, Cultured

KW - Humans

KW - Mice

KW - Models, Molecular

KW - Mutation

KW - Parkinson Disease

KW - Protein-Serine-Threonine Kinases

KW - Pyrimidines

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DO - 10.1016/j.bmcl.2012.01.084

M3 - Article

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EP - 1869

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

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ER -

Characterization of TAE684 as a potent LRRK2 kinase inhibitor

Abstract

Keywords

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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)

Cite this