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  • 1. SESSION IVWhat’s Druggable – Designing Drugs for CNSTarget ClassesChair — Mark Frasier, PhD, Michael J. Fox Foundation for Parkinson’sResearchSession OverviewMark Frasier, PhD, Michael J. Fox Foundation for Parkinson’s ResearchProtein-Protein Interaction: A Growing Trend Towards FeasibilityGérard Rossé, PhD, Dart NeuroscienceChallenges in Targeting Kinases for Neurodegenerative DiseasesRavi G. Kurumbail, PhD, Pfizer Inc.Druggability Considerations for GPCRs and Ion ChannelsShaun R. Stauffer, PhD, Vanderbilt UniversityBiologics for Challenging Targets: Unique Challenges and Lessons Learned
  • 2. What’s Druggable? Designing Drugs for CNS Target Classes ADDF Meeting February, 2012
  • 3. What is in the MJFF pipeline?  Disease-modification: Genetics (A-synuclein, LRRK2), inflammation, Nrf2, Nurr1, GDNF, CDNF, antioxidantsPromising targets  Symptomatic: mGluR5, mGluR4, nicotinic, mu opioid  Over 100 industry led projects moving to the clinic Preclinical  Dyskinesia therapies development  Translational research tools: animal models, antibodies, biomarkers  20 ongoing MJFF funded intervention trials  NTN gene therapy (Ceregene), A-synuclein (Affiris) Clinical trials  mGluR5 (Addex), Eltopazine, Dopaminergic improvements (NeuroDerm)  Repurposing: Pioglitazone, Inosine, Isradipine PD pipeline shows promise
  • 4. MJFF Resources  Transgenic mice, knockout rats  Standardized characterization Animal Models  Open access and central repository  Novel LRRK2 antibodies  Assay development and optimization Reagents  Accessible to the research community  Arizona Brain Bank collaboration – PD and other tissueHuman Tissue and  DATATOP (collaboration with PSG) – serum, urine, CSF and DNA Samples  PPMI and supporting studies – serum, plasma, whole blood, CSF, DNA, RNA and urine  Dyskinesia rating scale  Cognitive scalesClinical Trial Tools  Fox Trial Finder Critical tools to accelerate drug development
  • 5. Target Validation – Target X CATEGORY Untested/ Broad Target Organ Broad and Target OrganExpression & Activity Unknown Disease and Disease Modified Modified Untested/ In Vitro Pathway Ex Vivo In Vivo Beneficial Pre-Clinical Unknown Modulation Pathway Pathway Target Pharmacological Modulation Modulation Modulation In Target Modulation Vivo Untested/ Negative Result Model Rodent/Primat Human MutantNon-Human Genetic Unknown Upon Testing Organism e Relevant Relevant Modulation Relevant Phenotype Phenotype Phenotype Untested/ Single Study Multiple Study Genotype Human Genetic Unknown Association Association Phenotype Modulation Relationship Clinical Untested/ Negative Result Symptomatic Effective/Safe Effective/Safe in Pharmacological Unknown Upon Testing without known in Proof of Pivotal Trials target Concept Trials Target Modulation (non-PD) Clinical Untested/ Negative Result Symptomatic Effective/Safe Effective/Safe in Pharmacological Unknown Upon Testing without known in Proof of Pivotal Trials target Concept Trials Target Modulation (PD)
  • 6. AgendaGerard 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”
  • 7. 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
  • 8. Pathways of Drug Discovery Target & hit Hit refinement & Lead optimization IdentificationSelected Clinical Candidate Marketed Drug
  • 9. Decision Gates in Pre-Clinical Drug Discovery Advanced DC Drug Hits Leads (NDA) Leads (IND) Regulatory ReHit Generation Hit ExplorationChemical Optimization Pre- Development Target & hit Hit refinement Lead optimization clinical Identification studies Clinical studies Hit to Lead LO Validated Hit Identified Leads Fully Selected Launched Series Series Optimized Clinical Lead Candidate Stage-by-stage quality assessment. Reduce attrition rate, time and cost
  • 10. Genes Target Families Gene-family Distribution of Targets of top 200 selling Current Drugs prescription drugs (1997) #of #distinct Worldwide sales Protein family drugs targets ($US billions) GPCRs 27% GPCRs 38 25 21.3 Enzymes* 28 15 16.8 NHRs 13% Ion channels 28 5 12.0 NHRs 20 8 7.6 Ligand-gated Biotherapeutics 20 - 9.02 ion channels 9% Proteases 10 2 7.11 Voltage-gated Symporters 6 3 6.36 ion channels 5% Pumps 4 2 6.02 Unknown 11 - 3.71 *non-proteases Birkeland (IM) & Agarwal (BLX): Feb-99• 1,357 unique drugs (1204 small molecules & 166 biologics)• 324 drug targets for all classes of approved therapeutics drugs Challenging Targets:• 1,048 druggable targets (35% identity) Protein-Protein Interactions in human genome Overington et al. Nature Reviews Drug Discovery 5, 993–996, 2006
  • 11. Biochemical Space of Small Molecules Druggability/druggable target Feasibility 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 smallLipinski C.; A. Hopkins A. Nature, 432, 855, 2004 molecules that are intended to be orally administered. MW < 500, H-donor < 5, H-acceptorChemical space: 1060 (MW<500) < 10, clogP < 5
  • 12. Drug Platforms Therapeutic Limitations and “The Undruggables” Platform Advantages Disadvantages • Orally bioavailable • Inadequate selectivity Small Molecules • Cell/BBB permeable • Xenobiotic metabolism • Toxicity • Limited target binding sites • Undruggable targets • High specificity • Pharmacokinetics Peptides • Low toxicity • Cell/BBB impermeable • Block protein interactions • Undruggable targets • High specificity • Poor tissue penetration Biologics • Low toxicity • Cell/BBB impermeable • Block protein interactions • Immunogenicity • Limited target binding sites • Undruggable targets• 75-80% of all existing targets beyond reach of established drug platforms
  • 13. Protein-Protein Interaction (PPI)PPIs are a crucial element in cellular functionHuman diseases can be caused by aberrant PPIs: (i) loss of essentialinteraction (ii) formation/stabilization of protein complexAdvances in understanding mechanism of cell signaling are producinga growing number of potential therapeutic targetsPPIs may provide novel mechanisms to modulate (neural) functiondownstream of receptor activation or disrupt localization signals
  • 14. Rational for Targeting PPI in the CNS Amyloid Plaque NeurofibrillaryTangle • In the CNS a host of PPIs is required Formation in AD - 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 specificityStrategies for Neurodegenerative Diseases• Inhibiting protein aggregation• Targeting downstream members of signaling pathway
  • 15. Protein Misfolding/Aggregation in NeurodegenerationDisease Microscopic lesions Location Aggregated protein Amyloid plaque Extracellular Amyloid- (A )Alzheimer’s Neurofibrillary tangle Intra-cytoplasmic (neurons) Tau Lewy bodies Intra-cytoplasmic (neurons) -sinucleinParkinson’s Lewy bodies Intra-cytoplasmic (neurons) -sinuclein Neuronal intra-nuclear Huntingtin (containing polyHuntington’s and intra-cytoplasmic Intra-cytoplasmic (neurons) glutamine repeat inclusions expansion) SOD1 and neurofilamentALS Intra-cytoplasmic (neurons) SOD aggregates Disorders may share common targets for therapeutics development
  • 16. Emerging PPI Targets Downstream of Signaling Pathway • Selective G inhibitors (M119) • Potentiating GPCR signaling by inhibiting RGS proteins: - selective for specific GPCRs -effectors -effectors - tissue specific expression e.g. Adenyl e.g. PI3K - RGS4 widely expressed in CNS, inhibitors cyclase PLC PLC GIRK increase tissue specificity of an agonist MAPK Ca 2+• Significant hurdles in drug development: - cell/BBB permeability of compound - pathway selectivity (druggable networks)
  • 17. 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 PPI ModulationRecent 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
  • 18. 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 O F 3C NO2 H N S O O Bak, which may trigger mitochondrial- H H O N N S O O S N O N N S O O S N induced apoptosis O N N • Orally bioavailable analog, ABT-263, inCl ABT-737 Cl ABT-263 multiple Ph I for lymphoma, CLL, SCLC Vogler M. et al. Cell Death and Differentiation, 16, 360-367, 2009
  • 19. Fragment-Based Drug Discovery Fragments MW 120 - 250 Scaffolds MW 250 - 350 Hit compound MW 350 - 50010 mM 1 mM 100 M 10 M 1 M Affinity• 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
  • 20. Adapted from Future Medicinal Chemistry, April 2009, Vol. 1, No. 1, Pages 65-93 with permission of Future Science Ltd Mechanism of PPI Modulators Targeting hot-spots P2 P1P1 P2 Allosteric sites= Hot -spots= Small molecule= Allosteric site P1 P2 Adapted from Future Medicinal Chemistry, with permission of Future Science Ltd
  • 21. Mechanism of PPI ModulatorsStabilizing PPIs Ligand• 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
  • 22. PPI Drug Discovery Problem• Historically limited success in HTS of small molecule collections• PPIs very different from more established targets Q ui k Ti e™ and a c m dec om pr es s or ar e ne eded t o s e e t hi pi t u r e. s c• Current small molecule collections decorated in the wrong way• 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 modulatorsWells JC.; McClendon CL Nature, 450, 1001, 2007
  • 23. Strategies to Identify Small Molecules PPI Modulators HTS Peptides / Fragment-based Computational (small Peptidomimetics (MW < 250, Chemistry molecules & ( -helical, Ki ~ 100 M) (Hot spots, natural -strand, -turn) binding site) products) PPI ModulatorsChance only favors theprepared mind. — Louis Pasteur
  • 24. Project Discovery Flow HT Screening (PPI binding assay Phenotypic) Functional eADME Assay(s) Key Elements • Selection of compounds libraries • Choice of primary, secondary assay(s)PK, brain level Selectivity • Understanding selectivity and i.p., i.v., p.o. brain permeability • Multidisciplinary team PoC In vivo efficacy in rodent model
  • 25. Innovative Approaches to Target PPIs Small Molecule in Binding Pocket Antibody Binding Surface Protrusion Staples Peptides Miniature proteins PEM Synbody0 500 1,000 2,000 200,000 Molecular weight
  • 26. Future Perspective 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)