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Gilsbach, B.K.* ; Messias, A.C. ; Ito, G.* ; Sattler, M. ; Alessi, D.R.* ; Wittinghofer, A.* ; Kortholt, A.*

Structural characterization of LRRK2 inhibitors.

J. Med. Chem. 58, 3751-3756 (2015)
DOI
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Repeat Kinase 2; Transfer Difference Nmr; Parkinsons-disease; Protein-kinases; Highly Potent; Mutations; Discovery; Spectroscopy; Mechanism; Binding
ISSN (print) / ISBN 0022-2623
e-ISSN 1520-4804
Journal Journal of Medicinal Chemistry
Quellenangaben Volume: 58, Issue: 9, Pages: 3751-3756 Article Number: , Supplement: ,
Publisher American Chemical Society (ACS)
Publishing Place Washington
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)