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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 (IC(50) of 7.8nM against wild-type LRRK2, 6.1nM 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?M in cells and in mouse spleen and kidney, but not in brain, following oral doses of 10mg/kg.

SUBMITTER: Zhang J

PROVIDER: S-EPMC3433743 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Characterization of TAE684 as a potent LRRK2 kinase inhibitor.

Zhang Jinwei J Deng Xianming X Choi Hwan Geun HG Alessi Dario R DR Gray Nathanael S NS

Bioorganic & medicinal chemistry letters 20120128 5

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 (IC(50) of 7.8nM against wild-type LRRK2, 6.1nM against the G2019S mutant). TAE684 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentrat ...[more]

PMID: 22335897

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