The goal of this project is to develop a c-jun N-terminal kinase 2/3 (JNK2/3) inhibitor that may be used in thetreatment of neurodegeneration in Parkinson's disease (PD). Development of a drug that preventsdopaminergic neurodegeneration would be first in class for halting progression of the disease and a clinicalcomplement to existing medication used in symptomatic treatment of PD. We have assembled a team ofbiochemists, cell biologists, medicinal chemists, structural biologists, pharmacologists, analytical chemists,and behavioral pharmacologists with extensive pharmaceutical experience to execute this drug developmentprogram.
In Aim 1 (years 1-2) we will optimize JNK2/3 inhibitors to select a preclinical developmentcandidate. By the end of year 2 we anticipate having one or more compounds that: 1) are potent andselective JNK2/3 inhibitors, 2) promote primary dopaminergic neuronal survival, and 3) have goodpharmacokinetic properties and brain penetration.
This aim will be accomplished by utilizing medicinalchemistry and structure-based drug design supported by biochemical and cell-based assays, andpharmacokinetics to develop structure-activity-relationships (SAR). During Aim 2 (year 3) we willdemonstrate efficacy in MPTP-mouse models of PD for greater than or equal to three compounds,demonstrate lack of interaction with human CYP450s, and evaluate five to ten compounds in preliminarytoxicity studies. The reason for evaluating five to ten of our most promising compounds is to optimize thechance for clinical success and mitigate the risk of developing a single molecule that may fail indevelopment.
In Aim 3 (years 4-5) we will conduct Investigation New Drug enabling genotoxicity, safetypharmacology, and toxicology studies aimed at helping select a clinical candidate that has the best metabolicprofile and widest therapeutic index. Collectively these studies are intended at generating a lead clinicalcandidate (and back ups) that have sufficient data to meet Food and Drug Administration standards tosupport up through Phase II human clinical trials in Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01NS057153-01A2
Application #
7695912
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
2008-07-01
Project End
2013-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
1
Fiscal Year
2008
Total Cost
$1,503,665
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Iqbal, Sarah; Howard, Shannon; LoGrasso, Philip V (2015) Serum- and Glucocorticoid-Inducible Kinase 1 Confers Protection in Cell-Based and in In Vivo Neurotoxin Models via the c-Jun N-Terminal Kinase Signaling Pathway. Mol Cell Biol 35:1992-2006
He, Yuanjun; Duckett, Derek; Chen, Weimin et al. (2014) Synthesis and SAR of novel isoxazoles as potent c-jun N-terminal kinase (JNK) inhibitors. Bioorg Med Chem Lett 24:161-4
Chambers, Jeremy W; Howard, Shannon; LoGrasso, Philip V (2013) Blocking c-Jun N-terminal kinase (JNK) translocation to the mitochondria prevents 6-hydroxydopamine-induced toxicity in vitro and in vivo. J Biol Chem 288:1079-87
Chambers, Jeremy W; Pachori, Alok; Howard, Shannon et al. (2013) Inhibition of JNK mitochondrial localization and signaling is protective against ischemia/reperfusion injury in rats. J Biol Chem 288:4000-11
Feng, Yangbo; Chambers, Jeremy W; Iqbal, Sarah et al. (2013) A small molecule bidentate-binding dual inhibitor probe of the LRRK2 and JNK kinases. ACS Chem Biol 8:1747-54
Figuera-Losada, Mariana; LoGrasso, Philip V (2012) Enzyme kinetics and interaction studies for human JNK1?1 and substrates activating transcription factor 2 (ATF2) and c-Jun N-terminal kinase (c-Jun). J Biol Chem 287:13291-302
Laughlin, John D; Nwachukwu, Jerome C; Figuera-Losada, Mariana et al. (2012) Structural mechanisms of allostery and autoinhibition in JNK family kinases. Structure 20:2174-84
Zhang, Tinghu; Inesta-Vaquera, Francisco; Niepel, Mario et al. (2012) Discovery of potent and selective covalent inhibitors of JNK. Chem Biol 19:140-54
Chambers, Jeremy W; Pachori, Alok; Howard, Shannon et al. (2011) Small Molecule c-jun-N-terminal Kinase (JNK) Inhibitors Protect Dopaminergic Neurons in a Model of Parkinson's Disease. ACS Chem Neurosci 2:198-206
He, Yuanjun; Kamenecka, Theodore M; Shin, Youseung et al. (2011) Synthesis and SAR of novel quinazolines as potent and brain-penetrant c-jun N-terminal kinase (JNK) inhibitors. Bioorg Med Chem Lett 21:1719-23

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