Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disorder. Several single gene mutations have been linked to this disease. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) indicate LRRK2 as promising therapeutic target for the treatment of PD.
LRRK2 mutations were observed in sporadic as well as familial PD patients and have been investigated intensively. LRRK2 is a large and complex protein, with multiple enzymatic and protein-interaction domains, each of which is effected by mutations. The most common mutation in PD patients is G2019S.
Several LRRK2 inhibitors have been reported already, although the crystal structure of LRRK2 has not yet been determined. This review provides a summary of known LRRK2 inhibitors and will discuss recent in vitro and in vivo results of these inhibitors.
Citing Articles
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This article has been cited by 6 ACS Journal articles (5 most recent appear below).
Discovery of Highly Potent, Selective, and Brain-Penetrant Aminopyrazole Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule Inhibitors
Anthony A. Estrada, Bryan K. Chan, Charles Baker-Glenn, Alan Beresford, Daniel J. Burdick, Mark Chambers, Huifen Chen, Sara L. Dominguez, Jennafer Dotson, Jason Drummond, Michael Flagella, Reina Fuji, Andrew Gill, Jason Halladay, Seth F. Harris, Timothy P. Heffron, Tracy Kleinheinz, Donna W. Lee, Claire E. Le Pichon, Xingrong Liu, Joseph P. Lyssikatos, Andrew D. Medhurst, John G. Moffat, Kevin Nash, Kimberly Scearce-Levie, Zejuan Sheng, Daniel G. Shore, Susan Wong, Shuo Zhang, Xiaolin Zhang, Haitao Zhu, and Zachary K. SweeneyJournal of Medicinal Chemistry2014 57 (3), 921-936Discovery of Highly Potent, Selective, and Brain-Penetrant Aminopyrazole Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule Inhibitors
Anthony A.Estrada, Bryan K.Chan, CharlesBaker-Glenn, AlanBeresford, Daniel J.Burdick, MarkChambers, HuifenChen, Sara L.Dominguez, JennaferDotson, JasonDrummond, MichaelFlagella, ReinaFuji, AndrewGill, JasonHalladay, Seth F.Harris, Timothy P.Heffron, TracyKleinheinz, Donna W.Lee, Claire E. LePichon, XingrongLiu, Joseph P.Lyssikatos, Andrew D.Medhurst, John G.Moffat, KevinNash, KimberlyScearce-Levie, ZejuanSheng, Daniel G.Shore, SusanWong, ShuoZhang, XiaolinZhang, HaitaoZhu, and Zachary K.SweeneyJournal of Medicinal Chemistry2014 57 (3), 921-936Leucine-rich repeat kinase 2 (LRRK2) has drawn significant interest in the neuroscience research community because it is one of the most compelling targets for a potential disease-modifying Parkinson’s disease therapy. Herein, we disclose structurally ...
A Small Molecule Bidentate-Binding Dual Inhibitor Probe of the LRRK2 and JNK Kinases
Yangbo Feng, Jeremy W. Chambers, Sarah Iqbal, Marcel Koenig, HaJeung Park, Lisa Cherry, Pamela Hernandez, Mariana Figuera-Losada, and Philip V. LoGrassoACS Chemical Biology2013 8 (8), 1747-1754A Small Molecule Bidentate-Binding Dual Inhibitor Probe of the LRRK2 and JNK Kinases
YangboFeng, Jeremy W.Chambers, SarahIqbal, MarcelKoenig, HaJeungPark, LisaCherry, PamelaHernandez, MarianaFiguera-Losada, and Philip V.LoGrassoACS Chemical Biology2013 8 (8), 1747-1754Both JNK and LRRK2 are associated with Parkinson’s disease (PD). Here we report a reasonably selective and potent kinase inhibitor (compound 6) that bound to both JNK and LRRK2 (a dual inhibitor). A bidentate-binding strategy that simultaneously utilized ...
Type II Kinase Inhibitors Show an Unexpected Inhibition Mode against Parkinson’s Disease-Linked LRRK2 Mutant G2019S
Min Liu, Samantha A. Bender, Gregory D. Cuny, Woody Sherman, Marcie Glicksman, and Soumya S. RayBiochemistry2013 52 (10), 1725-1736Type II Kinase Inhibitors Show an Unexpected Inhibition Mode against Parkinson’s Disease-Linked LRRK2 Mutant G2019S
MinLiu, Samantha A.Bender, Gregory D.Cuny, WoodySherman, MarcieGlicksman, and Soumya S.RayBiochemistry2013 52 (10), 1725-1736A number of well-known type II inhibitors (ATP-noncompetitive) that bind kinases in their DFG-out conformation were tested against wild-type LRRK2 and the most common Parkinson’s disease-linked mutation, G2019S. We found that traditional type II ...
Discovery of a Highly Selective, Brain-Penetrant Aminopyrazole LRRK2 Inhibitor
Bryan K. Chan, Anthony A. Estrada, Huifen Chen, John Atherall, Charles Baker-Glenn, Alan Beresford, Daniel J. Burdick, Mark Chambers, Sara L. Dominguez, Jason Drummond, Andrew Gill, Tracy Kleinheinz, Claire E. Le Pichon, Andrew D. Medhurst, Xingrong Liu, John G. Moffat, Kevin Nash, Kimberly Scearce-Levie, Zejuan Sheng, Daniel G. Shore, Hervé Van de Poël, Shuo Zhang, Haitao Zhu, and Zachary K. SweeneyACS Medicinal Chemistry Letters2013 4 (1), 85-90Discovery of a Highly Selective, Brain-Penetrant Aminopyrazole LRRK2 Inhibitor
Bryan K.Chan, Anthony A.Estrada, HuifenChen, JohnAtherall, CharlesBaker-Glenn, AlanBeresford, Daniel J.Burdick, MarkChambers, Sara L.Dominguez, JasonDrummond, AndrewGill, TracyKleinheinz, Claire E.Le Pichon, Andrew D.Medhurst, XingrongLiu, John G.Moffat, KevinNash, KimberlyScearce-Levie, ZejuanSheng, Daniel G.Shore, HervéVan de Poël, ShuoZhang, HaitaoZhu, and Zachary K.SweeneyACS Medicinal Chemistry Letters2013 4 (1), 85-90The modulation of LRRK2 kinase activity by a selective small molecule inhibitor has been proposed as a potentially viable treatment for Parkinson's disease. By using aminopyrazoles as aniline bioisosteres, we discovered a novel series of LRRK2 inhibitors. ...
Discovery of Highly Potent, Selective, and Brain-Penetrable Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule Inhibitors
Anthony A. Estrada, Xingrong Liu, Charles Baker-Glenn, Alan Beresford, Daniel J. Burdick, Mark Chambers, Bryan K. Chan, Huifen Chen, Xiao Ding, Antonio G. DiPasquale, Sara L. Dominguez, Jennafer Dotson, Jason Drummond, Michael Flagella, Sean Flynn, Reina Fuji, Andrew Gill, Janet Gunzner-Toste, Seth F. Harris, Timothy P. Heffron, Tracy Kleinheinz, Donna W. Lee, Claire E. Le Pichon, Joseph P. Lyssikatos, Andrew D. Medhurst, John G. Moffat, Susmith Mukund, Kevin Nash, Kimberly Scearce-Levie, Zejuan Sheng, Daniel G. Shore, Thuy Tran, Naimisha Trivedi, Shumei Wang, Shuo Zhang, Xiaolin Zhang, Guiling Zhao, Haitao Zhu, and Zachary K. SweeneyJournal of Medicinal Chemistry2012 55 (22), 9416-9433
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