Structural Characterization of LRRK2 Inhibitors

Gilsbach, B. K., Messias, A. C., Ito, G., Sattler, M., Alessi, D. R., Wittinghofer, A. & Kortholt, A., 1-May-2015, In : Journal of Medicinal Chemistry. 58, 9, p. 3751−3756 6 p.

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  • Structural Characterization of LRRK2 Inhibitors

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  • Bernd K Gilsbach
  • Ana C Messias
  • Genta Ito
  • Michael Sattler
  • Dario R Alessi
  • Alfred Wittinghofer
  • Arjan Kortholt

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
Issue number9
Publication statusPublished - 1-May-2015

ID: 19579924