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Biochem Biophys Res Commun. 2009 Jan 16;378(3):473-7. doi: 10.1016/j.bbrc.2008.11.048. Epub 2008 Nov 21.

Identification of compounds that inhibit the kinase activity of leucine-rich repeat kinase 2.

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Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, 125 John Morgan Building, Philadelphia, PA 19104-6084, USA.

Erratum in

  • Biochem Biophys Res Commun. 2009 Sep 18;387(2):419-20.


Mutations in leucine-repeat rich kinase 2 (LRRK2) are the most common known cause of late-onset Parkinson's disease. In this study, a novel system to purify active recombinant LRRK2 expressed in mammalian cells was generated. This recombinant enzyme was used to characterize the specificity of LRRK2 and identify small compounds that can inhibit the kinase activity. Recombinant LRRK2 was shown to autophosphorylate and phosphorylate MBP and a peptide (LRRKtide) corresponding to the T558 [corrected] site in moesin. A series of well-characterized kinase peptide substrates was not modified by LRRK2 demonstrating remarkable specificity. G2019S, the most common disease-causing mutation in LRRK2, increased kinase activity more dramatically than previously appreciated ( approximately 10-fold). Several small molecules sharing a basic indolocarbazole structure (Gö6976, K-252a, and staurosporine) where identified as potent inhibitors of LRRK2 kinase activity. These findings provide important insights and tools to study the mechanisms of LRRK2 pathobiology, and could lead to therapeutic applications.

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