2014年10月7日火曜日

Small Molecule Kinase Inhibitors for LRRK2

Abstract



Abstract Image
 
 
 
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).
  • Cover Image

    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. Sweeney
    Journal of Medicinal Chemistry2014 57 (3), 921-936
    • Discovery 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.Sweeney
      Journal of Medicinal Chemistry2014 57 (3), 921-936
      Leucine-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 ...
  • Cover Image

    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. LoGrasso
    ACS Chemical Biology2013 8 (8), 1747-1754
    • A 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.LoGrasso
      ACS Chemical Biology2013 8 (8), 1747-1754
      Both 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 ...
  • Cover Image

    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. Ray
    Biochemistry2013 52 (10), 1725-1736
    • Type 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.Ray
      Biochemistry2013 52 (10), 1725-1736
      A 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 ...
  • Cover Image

    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. Sweeney
    ACS Medicinal Chemistry Letters2013 4 (1), 85-90
    • Discovery 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.Sweeney
      ACS Medicinal Chemistry Letters2013 4 (1), 85-90
      The 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. ...
  • Cover Image

    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. Sweeney
    Journal of Medicinal Chemistry2012 55 (22), 9416-9433

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