title: Novel LRRK2 GTP-binding inhibitors reduced degeneration in Parkinson's disease cell and mouse models.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
authors.forename: Tianxia
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
authors.forename: Dejun
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
authors.forename: Shijun
authors.initials: S
authors.lastname: Zhong
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Thomas
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
authors.forename: Fengtian
authors.initials: F
authors.lastname: Xue
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
authors.forename: Jingnan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
authors.forename: Lingbo
authors.initials: L
authors.lastname: Kong
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Voulalas
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
authors.forename: Hazem E
authors.initials: HE
authors.lastname: Hassan
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
authors.forename: Jae-Sung
authors.initials: JS
authors.lastname: Park
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: MacKerell
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA wsmith@rx.umaryland.edu.
authors.forename: Wanli W
authors.initials: WW
authors.lastname: Smith
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006160:Guanosine Triphosphate / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D008070:Lipopolysaccharides; D013450:Sulfones; D013844:Thiazoles; D006160:Guanosine Triphosphate; C510751:LRRK1 protein, human; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases