PMID- 24993787
OWN - NLM
STAT- MEDLINE
DCOM- 20151029
LR  - 20211203
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Linking)
VI  - 23
IP  - 23
DP  - 2014 Dec 1
TI  - Novel LRRK2 GTP-binding inhibitors reduced degeneration in Parkinson's disease 
      cell and mouse models.
PG  - 6212-22
LID - 10.1093/hmg/ddu341 [doi]
AB  - Mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause 
      autosomal-dominant Parkinson's disease (PD) and contribute to sporadic PD. LRRK2 
      contains Guanosine-5'-triphosphate (GTP) binding, GTPase and kinase activities 
      that have been implicated in the neuronal degeneration of PD pathogenesis, making 
      LRRK2, a potential drug target. To date, there is no disease-modifying drug to 
      slow the neuronal degeneration of PD and no published LRRK2 GTP domain inhibitor. 
      Here, the biological functions of two novel GTP-binding inhibitors of LRRK2 were 
      examined in PD cell and mouse models. Through a combination of computer-aided 
      drug design (CADD) and LRRK2 bio-functional screens, two novel compounds, 68: and 
      70: , were shown to reduce LRRK2 GTP binding and to inhibit LRRK2 kinase activity 
      in vitro and in cultured cell assays. Moreover, these two compounds attenuated 
      neuronal degeneration in human SH-SY5Y neuroblastoma cells and mouse primary 
      neurons expressing mutant LRRK2 variants. Although both compounds inhibited LRRK2 
      kinase activity and reduced neuronal degeneration, solubility problems with 70: 
      prevented further testing in mice. Thus, only 68: was tested in a LRRK2-based 
      lipopolysaccharide (LPS)-induced pre-inflammatory mouse model. 68: reduced LRRK2 
      GTP-binding activity and kinase activity in brains of LRRK2 transgenic mice after 
      intraperitoneal injection. Moreover, LPS induced LRRK2 upregulation and microglia 
      activation in mouse brains. These findings suggest that disruption of GTP binding 
      to LRRK2 represents a potential novel therapeutic approach for PD intervention 
      and that these novel GTP-binding inhibitors provide both tools and lead compounds 
      for future drug development.
CI  - (c) The Author 2014. Published by Oxford University Press. All rights reserved. For 
      Permissions, please email: journals.permissions@oup.com.
FAU - Li, Tianxia
AU  - Li T
AD  - Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 
      Baltimore, MD 21201, USA.
FAU - Yang, Dejun
AU  - Yang D
AD  - Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 
      Baltimore, MD 21201, USA.
FAU - Zhong, Shijun
AU  - Zhong S
AD  - Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 
      Baltimore, MD 21201, USA.
FAU - Thomas, Joseph M
AU  - Thomas JM
AD  - Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 
      Baltimore, MD 21201, USA.
FAU - Xue, Fengtian
AU  - Xue F
AD  - Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 
      Baltimore, MD 21201, USA.
FAU - Liu, Jingnan
AU  - Liu J
AD  - Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 
      Baltimore, MD 21201, USA.
FAU - Kong, Lingbo
AU  - Kong L
AD  - Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 
      Baltimore, MD 21201, USA.
FAU - Voulalas, Pamela
AU  - Voulalas P
AD  - Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 
      Baltimore, MD 21201, USA.
FAU - Hassan, Hazem E
AU  - Hassan HE
AD  - Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 
      Baltimore, MD 21201, USA.
FAU - Park, Jae-Sung
AU  - Park JS
AD  - Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 
      Baltimore, MD 21201, USA.
FAU - MacKerell, Alexander D Jr
AU  - MacKerell AD Jr
AD  - Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 
      Baltimore, MD 21201, USA.
FAU - Smith, Wanli W
AU  - Smith WW
AD  - Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 
      Baltimore, MD 21201, USA wsmith@rx.umaryland.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140703
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Sulfones)
RN  - 0 (Thiazoles)
RN  - 86-01-1 (Guanosine Triphosphate)
RN  - EC 2.7.11.1 (LRRK1 protein, human)
RN  - EC 2.7.11.1 (LRRK2 protein, human)
RN  - EC 2.7.11.1 (Leucine-Rich Repeat Serine-Threonine Protein Kinase-2)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Brain/drug effects/metabolism/pathology
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Guanosine Triphosphate/*metabolism
MH  - Humans
MH  - Inflammation/metabolism/pathology
MH  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
MH  - Lipopolysaccharides/pharmacology
MH  - Mice
MH  - Mice, Transgenic
MH  - Microglia/drug effects/metabolism/pathology
MH  - Mutation
MH  - Neurons/*drug effects/metabolism/pathology
MH  - Parkinson Disease/drug therapy/enzymology/*pathology
MH  - Phosphorylation
MH  - Protein Binding
MH  - Protein Serine-Threonine Kinases/*antagonists & inhibitors/genetics/metabolism
MH  - Sulfones/*pharmacology/therapeutic use
MH  - Thiazoles/*pharmacology/therapeutic use
EDAT- 2014/07/06 06:00
MHDA- 2015/10/30 06:00
CRDT- 2014/07/05 06:00
PHST- 2014/07/05 06:00 [entrez]
PHST- 2014/07/06 06:00 [pubmed]
PHST- 2015/10/30 06:00 [medline]
AID - ddu341 [pii]
AID - 10.1093/hmg/ddu341 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2014 Dec 1;23(23):6212-22. doi: 10.1093/hmg/ddu341. Epub 2014 Jul 
      3.