Structural characterization of LRRK2 inhibitors

Bernd K. Gilsbach, Ana C. Messias, Genta Ito, Michael Sattler, Dario R. Alessi, Alfred Wittinghofer, Arjan Kortholt (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    15 Citations (Scopus)

    Abstract

    Kinase inhibition is considered to be an important therapeutic target for LRRK2 mediated Parkinson's disease (PD). Many LRRK2 kinase inhibitors have been reported but have yet to be optimized in order to qualify as drug candidates for the treatment of the disease. In order to start a structure-function analysis of such inhibitors, we mutated the active site of Dictyostelium Roco4 kinase to resemble LRRK2. Here, we show saturation transfer difference (STD) NMR and the first cocrystal structures of two potent in vitro inhibitors, LRRK2-IN-1 and compound 19, with mutated Roco4. Our data demonstrate that this system can serve as an excellent tool for the structural characterization and optimization of LRRK2 inhibitors using X-ray crystallography and NMR spectroscopy.

    Original languageEnglish
    Pages (from-to)3751-3756
    Number of pages6
    JournalJournal of Medicinal Chemistry
    Volume58
    Issue number9
    DOIs
    Publication statusPublished - 14 May 2015

    Fingerprint Dive into the research topics of 'Structural characterization of LRRK2 inhibitors'. Together they form a unique fingerprint.

    Cite this