title: Small Molecule c-jun-N-terminal Kinase (JNK) Inhibitors Protect Dopaminergic Neurons in a Model of Parkinson's Disease.
abstract: There are currently no drugs to treat neurodegeneration in Parkinson's disease (PD) and all existing medications only treat symptoms, lose efficacy over time, and produce untoward side effects. In the current work, we report the first highly selective, orally bioavailable, c-jun-N-terminal kinase (JNK) inhibitor for protection of dopaminergic neurons in vitro and in vivo. At 300 nM this compound showed statistically significant protection of primary dopaminergic neurons exposed to 1-methyl-4-phenylpyridinium (MPP(+)), had pharmacokinetic properties in rodents consistent with twice daily (b.i.d.) dosing, and was orally efficacious at 30 mg/kg in a mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Moreover, a dose-dependent target modulation of c-jun phosphorylation served as a biomarker for demonstrating on-target inhibition of JNK as the mechanism of action for this compound. Collectively these results suggest that this JNK inhibitor could be a promising therapeutic neuroprotective agent in the treatment of Parkinson's disease.
authors.affiliation: Department of Molecular Therapeutics, and Translational Research Institute, The Scripps Research Institute, Scripps Florida, 130 Scripps Way #A2A, Jupiter, FL 33458.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Chambers
authors.forename: Alok
authors.initials: A
authors.lastname: Pachori
authors.forename: Shannon
authors.initials: S
authors.lastname: Howard
authors.forename: Michelle
authors.initials: M
authors.lastname: Ganno
authors.forename: Donald
authors.initials: D
authors.lastname: Hansen
authors.forename: Ted
authors.initials: T
authors.lastname: Kamenecka
authors.forename: Xinyi
authors.initials: X
authors.lastname: Song
authors.forename: Derek
authors.initials: D
authors.lastname: Duckett
authors.forename: Weimin
authors.initials: W
authors.lastname: Chen
authors.forename: Yuan Yuan
authors.initials: YY
authors.lastname: Ling
authors.forename: Lisa
authors.initials: L
authors.lastname: Cherry
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.forename: Claudia H
authors.initials: CH
authors.lastname: Ruiz
authors.forename: Philip
authors.initials: P
authors.lastname: Lograsso