Scripps Florida

1
Scripps Florida
Translational Research Institute

• Neurobiology
• Immune Disorders
• Infectious Diseases
• Chemistry

• Cell Based Screening
• RNA dynamics
• Genetics
• Proteomics

• Medicinal Chemistry
• uHTS
• Target Based Programs
• DMPK
• Animal Pharmacology
• Structural Biology
• Informatics

2
Translational Research Institute

• Advanced Technologies
• Genome Technologies
• Director - Hogenesch
• Protein Sciences
• Assoc Director - Busby
• Bioinformatics
• Sr. Director - Tsimoremas

• Drug Discovey
• Lead ID/HTS
• Head - Hodder
• Medicinal Chemistry
• Head - Roush
• Discovery Biology
• Head - LoGrasso
• Pharmacology
• Assoc Director - Smith
• DMPK
• Lab Head - Cameron
• CNS Disorders
• Director - Wahlestedt
• Informatics
• Sr. Director - Tsimoremas

3
DMPK Capabilities
Solubility
Rat or mouse PK IV/PO IP
Metabolic Stability human, rat, mouse, monkey,
canine
Tissue Distribution ie., brain penetration
Metabolite Profiling
Inhibition Screen (Cocktail at 10 µM)
P450 Phenotyping
Plasma Protein Binding (species)
Species Comparisons
IC50 10 isoforms
Induction mRNA Activity Ex vivo
Transporters and Transport Inhibition
Glutathione Adducts
Mechanism Based Inactivation
4
Research Operating Plan for JNK 2/3 Inhibitor
Development
Biochemical Counterscreen -vs- p38 and
JNK1 gt100-fold selective
Cell-based assay for c-jun phosphorylation IC50 lt
200 nM
JNK Biochemical Assay IC50 lt 10 nM
GO/NO GO
In vivo PK and Bioanalytical Development (Cmax,
AUC, t1/2)
Physiochemical Properties, Microsomal
Stability, CYP450 inhibition screening
Primary Dopaminergic Survival Assay IC50 lt 200 nM
In vivo Target Modulation IC50 lt 200 nM
MPTP Efficacy
Inhibition of 9 CYP450s IC50 gt 1000 nM
In vivo PK for dose linearity Cmax gt 2x ED95
Kinase panel Panlab Screen iKr, etc
Metabolite Identification in vitro and in vivo
CYP450 Phenotyping
5-day toxicology screen Formulation
Mutagenicity Genotoxicity Functional
HERG GLP Toxicology in two species
5
Research Operating Plan for JNK 2/3 Inhibitor
Development
Biochemical Counterscreen -vs- p38 and
JNK1 gt100-fold selective
Cell-based assay for c-jun phosphorylation IC50 lt
200 nM
JNK Biochemical Assay IC50 lt 10 nM
Appropriate Biochemical and Cellular
Activity/Selectivity
GO/NO GO
In vivo PK and Bioanalytical Development (Cmax,
AUC, t1/2)
Physiochemical Properties, Microsomal
Stability, CYP450 inhibition screening
Appropriate Physical Properties And PK
Primary Dopaminergic Survival Assay IC50 lt 200 nM
In vivo Target Modulation IC50 lt 200 nM
Efficacy and PK/PD
MPTP Efficacy
Inhibition of 9 CYP450s IC50 gt 1000 nM
In vivo PK for dose linearity Cmax gt 2x ED95
Kinase panel Panlab Screen
Appropriate Safety Liabilities Monitored
Metabolite Identification in vitro and in vivo
CYP450 Phenotyping
5-day toxicology screen Formulation
In vivo Tox
Mutagenicity Genotoxicity Functional
HERG GLP Toxicology in two species
Safety Pharmacology
6
Drug Discovery

• Discovery Programs
• Kinase Programs LoGrasso and Liang
• Cancer, neurodegeneration
• GPCR Programs - Wahlestedt
• Neurodegeneration, metabolic disorders
• Protease Program - LoGrasso
• Cardiovascular
• Current Industrial Collaborations
• Kinase program with NeoRx
• NR ligand profiling with Pharma
• Several compounds from 2 kinase programs -
  Exclusively Licensed by Novartis