Alzheimer's Disease Final Presentation
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Transcript of Alzheimer's Disease Final Presentation
![Page 1: Alzheimer's Disease Final Presentation](https://reader036.fdocuments.us/reader036/viewer/2022062400/587ba3311a28ab81758b5563/html5/thumbnails/1.jpg)
Neuro Group: Discovery of new secretase inhibitor drug leads for
neurodegeneration and Alzheimer's disease. Mission Statement & Timeline
Dorothy Du, Cathy Hutchinson and Melissa McCoy
Advisor: Gilbert Rishton, PhD
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Mission Statement
• To address the unmet medical need in Alzheimer's disease by the discovery and development of safe and effective drug leads and, ultimately, to help bring new mechanism-based medicines to the Alzheimer's disease patient population.
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Discovery• Alzheimer’s disease introduction
– Disease history and outlook, market analysis of current treatments on the market and in development (i.e. gamma-secretase inhibitors, Amyloid specific mAb, ect.), pro’s/con’s of current treatments and need for more drug development
• Neurodegeneration• What causes it in AD? What is the hypothesized disease pathway and
what factors are still not well understood?• APP, β-secretase, and A plaques
• Secretase inhibitor design from APP structure– Gil’s example of small molecule drug design
• Biochemical screening– Model Systems for testing efficacy (i.e. transfected cell lines, transgenic
mouse model of AD, ELISA for detecting Beta Amyloid levels)– Methods for screening blood-brain barrier permeability (computational,
in vivo, and in vitro methods)
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Figure 1 – Actual and estimated number of new AD cases in the US through 2050
Figure 2- Actual and estimated costs of AD in the US. Purple bars =Medicare costs, Yellowbars=Medicaid cost
Mount, Claire & Downton, Christian. Nature Medicine. 12, 780-784 (2006)
Disease Outlook
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Drug Company Mechanism IndicationAricept (donepezil)
Eisai/ Pfizer AChE inhibitor Mild to moderate AD
Exelon (rivastigmine)
Novartis AchE inhibitor Mild to moderate AD
Razadyne (galantamine)
Johnson and Johnson
AchE inhibitor Mild to moderate AD
Namenda/ Ebixa (memantine)
Lundbeck/ Forest NMDA receptor antagonist
Moderate to severe AD
Current Treatment Market
Figure 3- Existing and forecasted Alzheimer’s disease treatment marketMount, Claire & Downton, Christian. Nature Medicine. 12, 780-784 (2006)
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APP and β-Secretase• APP= Amyloid Precursor Protein
– Genetic link in Alzheimer’s Disease
• Protein is cleaved by enzymes known as secretases
– 3 types: α-secretase, β-secretase, and γ-secretase– Cleave the protein at different positions
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Familial Alzheimer’s Disease Sporadic Alzheimer’s Disease
Mutations in APP/Presenilin genes
Genetic risk factors:ApoE4, other genes? Aging & environmental
Life-long increase in Aβ42 production Failure of Aβ clearance, gradual increasing levels
Aβ accumulation and oligomerization
Aβ oligomers subtly effect synapses
Aβ oligomers form plaques
Immune cell activation/ inflammation
Oxidative stress/ altered ion flow
Neuron dysfunction/transmitter deficits
Dementia
Amyloid Cascade Hypothesis
Blennhow, Kaj et al. The Lancet. 368 (2006)
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Normal Tau Protein
Abnormally hyperphosphorylated tau
Kinases Phosphatases
Sequestration of MAPs and tau by hyperphosphorylated tau
Tau polymerization
NFT formation
Microtubule disassembly
Disturbed axonal flow/transport
Dementia
Neuronal dysfunction
Neuronal Death
Tau Protein in Alzheimer’s Disease
Blennhow, Kaj et al. The Lancet. 368 (2006)
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Potential Drug Targets of AD
Journal of Pharmacology And Experimental Therapeutics Fast Forward First published on November 25, 2002; DOI: 10.1124/jpet.102.035840
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Link Between Amyloid Hypothesis and Tau Protein
Journal of Pharmacology And Experimental Therapeutics Fast Forward First published on November 25, 2002; DOI: 10.1124/jpet.102.035840
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Competitive LandscapeDrug Target/Mechanism Company Stage of Development
β-secretase inhibitor Amgen, Bristol-Meyer Squibbs, Elan Pharmaceuticals, Scios Inc, GlaxoSmithKline
Pre-clinical
γ-secretase inhibitors or modulators
Eli Lilly, Myriad Pharmaceuticals
Phase II/III
Aβ immunotherapy Elan Pharmaceuticals, Baxter Healthcare, Wyeth
Phase I, II and III
Aβ fibrillization inhibitors Neurochem, Prana Biotechnology
Phase II/III
CDK5/GSK-3β inhibitors UCSB Pre-clinical
Anti-inflammatory drugs Proctor & Gamble, Roche Phase III
Cholesterol lowering drugs Pfizer Phase II
http://www.alzforum.org
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Why Target β-secretase?
• Plays a crucial role in the first step of the amyloid cascade
• Mice missing the β-secrectase gene are normal and cannot produce Aβ
• The enzyme is an aspartic protease similar to the HIV protease for which successful inhibitors have already been produced
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Biochemical Screening
• Biochemical Assay– Kinetic measurements-
determines how potent the inhibitor is
– β-Secretase FRET Assay ( Fluorescence Resonance
Energy Transfer) Inhibition of β-secretase by a Statine-derived Inhibitor.
http://www.invitrogen.com/content/sfs/manuals/L0724.pdf
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Biochemical Screening• Functional Activity Assays
– Utilize in vivo modelsystem:
• Transfected cell line• Transgenic mouse• Both produce excess Aβ
– Detect levels of Aβ in cell lysate or brain tissue
• Utilize immuno-assays• Western Blot, ELISA,
Immunoprecipitation
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Rational Methods
• Medicinal Chemistry• X-ray Crystallography, Co-crystallization• Assay Development
– Enzyme Assay Development to measure pharmacokinetics of drug leads
– Need to measure initial velocity of reaction, Km and Vmax with selected substrates
– Determine IC50 and Ki for inhibitors (used to determine how good the inhibitor is at inhibiting the enzyme and what type of inhibition is occuring)
– Assay would be an In vitro system that measures the ability of the drug lead to inhibit secretase
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Assay Development
• Biochemical Screening• Blood Brain Barrier Permeability (BBB)
– In vivo (transgenic mice) and in vitro (artificial membranes) approaches
– Computational approaches
• Other important Factors to Consider:– Pharmacokinetics-metabolic stability, metabolic liability,
permeability, protein binding– ADME- Absorption, Distribution, Metabolism and Excretion– Toxicology- will need to be outsourced
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Literature
• Patent search– Lead molecules, composition-of-matter patents
• Novelty, new intellectual property• Building cost at CSUCI
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Patent• Provisional patent
– Specific claims, composition-of-matter, use, function
– Structure, structure-activity-relationship– New drug lead, secretase inhibitor
• IP: Develop intellectual property position– Provisional patents– PCT patents
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Development
• Facilitate development by attention to quality in discovery stage– Leadlike, druglike, low MW, oral bioavailability,
blood-brain barrier permeability• Facilitate development by partnering
– Use contract development labs for in vivo work.– Partner with a drug company for clinical
development
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Characteristics of a Good Lead
Pajouhesh, Hassan et al. NeuroRx. 2, 541-553. (2005)