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

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    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 languageEnglish
    Pages (from-to)658-662
    Number of pages5
    JournalACS Medicinal Chemistry Letters
    Volume3
    Issue number8
    DOIs
    Publication statusPublished - 9 Aug 2012

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