title: Small-Molecule Inhibitors of LRRK2.
abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) protein have been genetically and functionally linked to Parkinson's disease (PD). The kinase activity of LRRK2 is increased by pathogenic mutations; therefore, modulation of LRRK2 kinase activity by a selective small-molecule inhibitor has been proposed as a potentially viable treatment for Parkinson's disease. This chapter presents a historical overview of the development and bioactivity of several small-molecule LRRK2 inhibitors that have been used to inhibit LRRK2 kinase activity in vitro or in vivo. These compounds are important tools for understanding the cellular biology of LRRK2 and for evaluating the potential of LRRK2 inhibitors as disease-modifying PD therapies.
authors.affiliation: Department of Cancer Biology, Dana Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Hatcher
authors.affiliation: New Drug Development Center, Daegu Gyeongbuk Medical Innovation Foundation, 80 Cheombok-ro, Dong-gu, Daegu, 41061, South Korea.
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Sir James Black Centre, Dow Street, Dundee, DD1 5EH, UK.
authors.forename: Dario R
authors.initials: DR
authors.lastname: Alessi
authors.affiliation: Department of Cancer Biology, Dana Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA. nathanael_gray@dfci.harvard.edu.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D000818:Animals; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000037:antagonists & inhibitors*; D010300:Parkinson Disease; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
keywords: LRRK2 inhibitors; Leucine-rich repeat kinase 2 (LRRK2); Mutations; Parkinson’s disease