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SESSION IV
What’s Druggable – Designing Drugs for CNS
Target Classes
Chair — Mark Frasier, PhD, Michael J. Fox Foundation for Parkinson’s
Research
Session Overview
Mark Frasier, PhD, Michael J. Fox Foundation for Parkinson’s Research
Protein-Protein Interaction: A Growing Trend Towards Feasibility
Gérard Rossé, PhD, Dart Neuroscience
Challenges in Targeting Kinases for Neurodegenerative Diseases
Ravi G. Kurumbail, PhD, Pfizer Inc.
Druggability Considerations for GPCRs and Ion Channels
Shaun R. Stauffer, PhD, Vanderbilt University
Biologics for Challenging Targets: Unique Challenges and Lessons Learned
Guriq S. Basi, PhD, Elan Pharmaceuticals, Inc.
What’s Druggable? Designing Drugs for CNS Target Classes
ADDF MeetingFebruary, 2012
What is in the MJFF pipeline?
Clinical trials
20 ongoing MJFF funded intervention trials
NTN gene therapy (Ceregene), A-synuclein (Affiris)
mGluR5 (Addex), Eltopazine, Dopaminergic improvements (NeuroDerm)
Repurposing: Pioglitazone, Inosine, Isradipine
Promising targets
Disease-modification: Genetics (A-synuclein, LRRK2), inflammation, Nrf2, Nurr1, GDNF, CDNF, antioxidants
Symptomatic: mGluR5, mGluR4, nicotinic, mu opioid
Preclinical development
Over 100 industry led projects moving to the clinic
Dyskinesia therapies
Translational research tools: animal models, antibodies, biomarkers
PD pipeline shows promise
MJFF Resources
Human Tissue and Samples
Arizona Brain Bank collaboration – PD and other tissue
DATATOP (collaboration with PSG) – serum, urine, CSF and DNA
PPMI and supporting studies – serum, plasma, whole blood, CSF, DNA, RNA and urine
Animal Models
Transgenic mice, knockout rats
Standardized characterization
Open access and central repository
Reagents
Novel LRRK2 antibodies
Assay development and optimization
Accessible to the research community
Critical tools to accelerate drug development
Clinical Trial Tools
Dyskinesia rating scale
Cognitive scales
Fox Trial Finder
Target Validation – Target XCATEGORY
Expression & Activity
Untested/
Unknown
Broad Target Organ Broad and
Disease
Modified
Target Organ
and Disease
Modified
Pre-Clinical
Pharmacological
Target Modulation
Untested/
Unknown
In Vitro Pathway
Modulation
Ex Vivo
Pathway
Modulation
In Vivo
Pathway
Modulation
Beneficial
Target
Modulation In
Vivo
Non-Human Genetic
Modulation
Untested/
Unknown
Negative Result
Upon Testing
Model
Organism
Relevant
Phenotype
Rodent/Primat
e Relevant
Phenotype
Human Mutant
Relevant
Phenotype
Human Genetic
Modulation
Untested/
Unknown
Single Study
Association
Multiple Study
Association
Genotype
Phenotype
Relationship
Clinical
Pharmacological
Target Modulation
(non-PD)
Untested/
Unknown
Negative Result
Upon Testing
Symptomatic
without known
target
Effective/Safe
in Proof of
Concept Trials
Effective/Safe in
Pivotal Trials
Clinical
Pharmacological
Target Modulation
(PD)
Untested/
Unknown
Negative Result
Upon Testing
Symptomatic
without known
target
Effective/Safe
in Proof of
Concept Trials
Effective/Safe in
Pivotal Trials
Agenda
Gerard Rosé, PhD: “Protein-Protein Interaction: A Growing Trend Towards Feasibility”
Ravi Kurumbail, PhD: “Challenges in Targeting Kinases for Neurodegenerative Diseases”
Shaun Stauffer, PhD “Druggability Considerations for GPCRs and Ion Channels”
Guriq Basi, PhD “Biologics for Challenging Targets: Unique Challenges and Lessons Learned”
Protein-Protein Interaction: A
Growing Trend Towards
Feasibility
Gérard Rossé, Ph.D., Dart Neuroscience
San Diego, CA
6th DRUG DISCOVERY FOR NEURODEGENERATION
CONFERENCE:
An Intensive Course on Translating Research into Drugs
New York, February 12-14, 2012
Pathways of Drug Discovery
Target & hit
Identification
Marketed Drug
Hit refinement & Lead optimization
Selected Clinical Candidate
Target & hitIdentification
Hit Generation
Hit refinement
Hit Exploration
Lead optimizationstudies
Chemical Optimization
Decision Gates in Pre-Clinical
Drug Discovery
Stage-by-stage quality assessment. Reduce attrition rate, time and cost
Hits LeadsDC(IND)
Validated Hit
Series
Drug(NDA)
Re
Identified Leads
Series
Selected
Clinical
Candidate
Launched
Hit to LeadLO
Advanced
Leads
RegulatoryDevelopment
Clinical studies
Fully
Optimized
Lead
Pre-clinical
Genes Target Families
• 1,357 unique drugs (1204 small
molecules & 166 biologics)
• 324 drug targets for all classes of
approved therapeutics drugs
• 1,048 druggable targets (35% identity)
in human genome
GPCRs 27%
Gene-family Distribution of
Current Drugs
NHRs 13%
Ligand-gated
ion channels 9%
Voltage-gated
ion channels 5%
Overington et al. Nature Reviews Drug Discovery 5, 993–996, 2006
Targets of top 200 selling
prescription drugs (1997)
Protein family
#ofdrugs
#distincttargets
Worldwide sales($US billions)
Birkeland (IM) & Agarwal (BLX): Feb-99
GPCRs
Enzymes*
Ion channels
NHRs
Biotherapeutics
Proteases
Symporters
Pumps
Unknown
38
28
28
20
20
10
6
4
11
25
15
5
8
-
2
3
2
-
21.3
16.8
12.0
7.6
9.02
7.11
6.36
6.02
3.71
*non-proteases
Challenging Targets:
Protein-Protein Interactions
Biochemical Space of Small Molecules
Lipinski C.; A. Hopkins A. Nature, 432, 855, 2004
Druggability/druggable targetFeasibility with which a macromolecular
target can be modulated by a small molecule
that has appropriate properties to be
developed into a drug
Rule of five (Lipinski’s rule)Key properties that should be considered for small
molecules that are intended to be orally
administered. MW < 500, H-donor < 5, H-acceptor
< 10, clogP < 5Chemical space: 1060 (MW<500)
Biologics
Peptides
Small Molecules• Orally bioavailable
• Cell/BBB permeable
• Inadequate selectivity
• Xenobiotic metabolism
• Toxicity
• Limited target binding sites
• Undruggable targets
• High specificity
• Low toxicity
• Block protein interactions
• Poor tissue penetration
• Cell/BBB impermeable
• Immunogenicity
• Limited target binding sites
• Undruggable targets
• High specificity
• Low toxicity
• Block protein interactions
• Pharmacokinetics
• Cell/BBB impermeable
• Undruggable targets
Drug Platforms
Therapeutic Limitations and “The Undruggables”
• 75-80% of all existing targets beyond reach of established drug platforms
Advantages DisadvantagesPlatform
Protein-Protein Interaction (PPI)
PPIs are a crucial element in cellular function
Advances in understanding mechanism of cell signaling are producing
a growing number of potential therapeutic targets
PPIs may provide novel mechanisms to modulate (neural) function
downstream of receptor activation or disrupt localization signals
Human diseases can be caused by aberrant PPIs: (i) loss of essential
interaction (ii) formation/stabilization of protein complex
Rational for Targeting PPI in the CNS
• In the CNS a host of PPIs is required
- neurite outgrowth
- synaptic formation
- signal transduction, neurotransmission
- apoptosis
• PPIs may provide novel mechanisms
to - modulate neural function downstream of
receptor activation
- disrupt localization signals
• Provide a measure of tissue specificity
Amyloid Plaque
NeurofibrillaryTangle
Formation in AD
• Inhibiting protein aggregation
• Targeting downstream members of signaling pathway
Strategies for Neurodegenerative Diseases
Protein Misfolding/Aggregation in
Neurodegeneration
Disease Microscopic lesions Location Aggregated protein
Alzheimer’s
Amyloid plaque
Neurofibrillary tangle
Lewy bodies
Extracellular
Intra-cytoplasmic (neurons)
Intra-cytoplasmic (neurons)
Amyloid- (A )
Tau
-sinuclein
Parkinson’s Lewy bodies Intra-cytoplasmic (neurons) -sinuclein
Huntington’s
Neuronal intra-nuclear
and intra-cytoplasmic
inclusions
Intra-cytoplasmic (neurons)
Huntingtin
(containing poly
glutamine repeat
expansion)
ALSSOD1 and neurofilament
aggregatesIntra-cytoplasmic (neurons) SOD
Disorders may share common targets for therapeutics development
Emerging PPI Targets Downstream of
Signaling Pathway
• Significant hurdles in drug development:
- cell/BBB permeability of compound
- pathway selectivity (druggable networks)
• Selective G inhibitors (M119)
• Potentiating GPCR signaling by inhibiting
RGS proteins:
- selective for specific GPCRs
- tissue specific expression
- RGS4 widely expressed in CNS, inhibitors
increase tissue specificity of an agonist
-effectors
e.g.
Adenyl
cyclase
PLC
MAPK
-effectors
e.g.
PI3K
PLC
GIRK
Ca 2+
PPI
Modulation
Recent Breakthrough:
- Stability of PPI complex is determined by only a small number of
amino acids: proteins “hot spots” (600 Å2)
- Success stories of small molecules PPI inhibitors in oncology
PPI modulation:
An Unsurmontable Problem?
Challenges:
- Large protein-protein contact surfaces (1500-3000 Å2), flat PP
interfaces and lack of suitable binding pockets, IUPs
- Low success rate in HTS campaigns
Evidence of PPI Target Class Tractability
• BCL-2 family protein previously thought to
be undruggable
• ABT-737 is a specific inhibitor of protein-
protein interaction (PPI), (Ki < 1 nM against
Bcl-2, Bcl-xL, Bcl-w)
• Prevent binding of the anti-apoptotic
proteins to apoptotic effectors Bax and
Bak, which may trigger mitochondrial-
induced apoptosis
• Orally bioavailable analog, ABT-263, in
multiple Ph I for lymphoma, CLL, SCLC
Vogler M. et al. Cell Death and Differentiation, 16, 360-367, 2009
N
N
Cl
OHN
S
HN
NO2
N
O OS
ABT-737
N
N
Cl
OHN
S
O
S
N
O OS
ABT-263
F3CO
O
O
Fragment-Based Drug Discovery
• A fragment is just a small weak hit; detection of weak binders
• Find small fragments, then grow/merge fragments to create hit.
• A small number of fragments can sample a large chemical space
- 103 fragments of MW 190 are equivalent to 1018 compounds of MW 450
• Requires protein structure to generate SAR for MedChem efforts
Fragments MW 120 - 250
10 mM 1 mM 100 M 10 M 1 M
Hit compound MW 350 - 500
Scaffolds MW 250 - 350
Affinity
P2
P2
Mechanism of PPI Modulators
= Hot -spots
P1
Targeting hot-spots
= Small molecule
P1
P1
Allosteric sites
P2= Allosteric site
Adapted from Future Medicinal Chemistry, April 2009, Vol. 1, No. 1, Pages 65-93 with permission of Future Science Ltd
Adapted from Future Medicinal Chemistry, with permission of Future Science Ltd
• Two classes of molecules: bifunctional compounds (rapamycin) or
2 moieties linked together
• Thermodynamic aspects of stabilization favorable
• Drawback of PPI stabilizers is large molecular size and weight
Stabilizing PPIs
Mechanism of PPI Modulators
Ligand
Q u ic k T im e ™ a n d a d e c o m p r e s s o r
a r e n e e d e d t o s e e t h is p ic t u r e .
• Historically limited success in HTS of small molecule collections
• PPIs very different from more established targets
• Current small molecule collections decorated in the wrong way
PPI Drug Discovery Problem
• Where is the biologically relevant chemical space of PPIs?
- MW > 500 for PPI inhibitors reaching clinical trial
- Predicted MW of 650-700 Da for small molecule PPI modulators
Wells JC.; McClendon CL Nature, 450, 1001, 2007
HTS(small
molecules &
natural
products)
PPI Modulators
Strategies to Identify Small Molecules
PPI Modulators
Peptides / Peptidomimetics
( -helical,
-strand, -turn)
Fragment-based
(MW < 250,
Ki ~ 100 M)
Chance only favors theprepared mind. — Louis Pasteur
Computational
Chemistry(Hot spots,
binding site)
Project Discovery Flow
HT Screening(PPI binding assay
Phenotypic)
Functional
Assay(s)eADME
PK, brain level
i.p., i.v., p.o.Selectivity
In vivo efficacy in
rodent model
• Selection of compounds libraries
• Choice of primary, secondary
assay(s)
• Understanding selectivity and
brain permeability
• Multidisciplinary team
Key Elements
PoC
Innovative Approaches to Target PPIs
Small Molecule in
Binding Pocket
Antibody Binding
Surface Protrusion
0 500 1,000 200,0002,000
Molecular weight
Staples Peptides
PEM
Synbody
Miniature proteins
Despite significant progress (e.g. oncology),
substantial challenges lie ahead in development of
PPI modulators
Druggability of PPI targets depends heavily on
advances in technologies:
- Improved assays to assess PPI modulators
- High-resolution structure prediction, molecular design
- Design and synthesis of compound libraries for PPIs
screening
- Drug delivery to CNS (neuronal uptake mechanism)
Future Perspective