title: Chemoproteomics-based design of potent LRRK2-selective lead compounds that attenuate Parkinson's disease-related toxicity in human neurons.
abstract: Leucine-rich repeat kinase-2 (LRRK2) mutations are the most important cause of familial Parkinson's disease, and non-selective inhibitors are protective in rodent disease models. Because of their poor potency and selectivity, the neuroprotective mechanism of these tool compounds has remained elusive so far, and it is still unknown whether selective LRRK2 inhibition can attenuate mutant LRRK2-dependent toxicity in human neurons. Here, we employ a chemoproteomics strategy to identify potent, selective, and metabolically stable LRRK2 inhibitors. We demonstrate that CZC-25146 prevents mutant LRRK2-induced injury of cultured rodent and human neurons with mid-nanomolar potency. These precise chemical probes further validate this emerging therapeutic strategy. They will enable more detailed studies of LRRK2-dependent signaling and pathogenesis and accelerate drug discovery.
authors.forename: Nigel
authors.initials: N
authors.lastname: Ramsden
authors.forename: Jessica
authors.initials: J
authors.lastname: Perrin
authors.forename: Zhao
authors.initials: Z
authors.lastname: Ren
authors.forename: Byoung Dae
authors.initials: BD
authors.lastname: Lee
authors.forename: Nico
authors.initials: N
authors.lastname: Zinn
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.forename: Danny
authors.initials: D
authors.lastname: Tam
authors.forename: Michael
authors.initials: M
authors.lastname: Bova
authors.forename: Manja
authors.initials: M
authors.lastname: Lang
authors.forename: Gerard
authors.initials: G
authors.lastname: Drewes
authors.forename: Marcus
authors.initials: M
authors.lastname: Bantscheff
authors.forename: Frederique
authors.initials: F
authors.lastname: Bard
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.forename: Carsten
authors.initials: C
authors.lastname: Hopf
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015195:Drug Design; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D009154:Mutation; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D040901:Proteomics / Q000379:methods*; D051381:Rats
chemical_list: D047428:Protein Kinase Inhibitors; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases