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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)
Verlagsversion DOI
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
Quellenangaben Band: 58, Heft: 9, Seiten: 3751-3756 Artikelnummer: , Supplement: ,
Verlag American Chemical Society (ACS)
Verlagsort Washington
Begutachtungsstatus Peer reviewed