Structural characterization of LRRK2 inhibitors

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

doi:10.1021/jm5018779

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 journal › Article › peer-review

32 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 language	English
Pages (from-to)	3751-3756
Number of pages	6
Journal	Journal of Medicinal Chemistry
Volume	58
Issue number	9
DOIs	https://doi.org/10.1021/jm5018779
Publication status	Published - 14 May 2015

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/jm5018779

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title = "Structural characterization of LRRK2 inhibitors",

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.",

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T1 - Structural characterization of LRRK2 inhibitors

AU - Gilsbach, Bernd K.

AU - Messias, Ana C.

AU - Ito, Genta

AU - Sattler, Michael

AU - Alessi, Dario R.

AU - Wittinghofer, Alfred

AU - Kortholt, Arjan

PY - 2015/5/14

Y1 - 2015/5/14

N2 - 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.

AB - 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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Structural characterization of LRRK2 inhibitors

Abstract

ASJC Scopus subject areas

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Role of fbx07 in Parkinson's Disease (Studentship)

Aref#d: 21286. Mass Spectrometry-Based Global Analysis of Protein Phosphorylation in Cells and Tissue Extracts with Altered PINK1 Catalytic Activity: A Novel Screen for PINK1 Substrates

Cite this

Structural characterization of LRRK2 inhibitors

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Projects

Role of fbx07 in Parkinson's Disease (Studentship)

Aref#d: 21286. Mass Spectrometry-Based Global Analysis of Protein Phosphorylation in Cells and Tissue Extracts with Altered PINK1 Catalytic Activity: A Novel Screen for PINK1 Substrates

Cite this