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Innovation and the life sciences
Dr Claes Wilhelmsson
Executive Director Research & Development
Scientific challenges
The challenges of new treatment paradigms
Cure
Disease prevention
Stop disease progression
Symptomatic treatment
Increasing safety and delivery convenience
Individualised, coupled to diagnosis
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Tailored Treatment
Disease Mechanism
Diagnostic
Target
Right Patient
Right Drug
Optimal Dose
Optimal Delivery
Optimal Therapy
The Ultimate Therapy: Prevention or Cure
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“The ultimate challenge for life science discover drugs/treatment paradigms to alleviate
or cure human disease”
1. Proteins
2. Antibodies
3. Gene therapy
4. Xenotransplantation
5. Antisense
6. Vaccines
7. Natural products
8. Low molecular weight synthetic drugs
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Medicinal
Chemistry
Pharmacology
Bioscience
High Throughput
Screening
Drug metabolism
- pharmacokinetics
- bioanalysis
Target Protein
Production
Molecular
Biology
Product
Toxicology/
Safety Assessment
Pharmaceutical &
Analytical R&D
Genetics
Commercial
Input
Process
R&D
Medical
input
Regulatory
Patents
Multi-disciplincary teamworking - our key to success
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Enabling Science & Technology (EST) integration
EST Chemistry
RAs
Target
Identification
• genetics
EST Biology
EST Informatics
structural
chemistry
screening
Target
Compound
Compound
Validation
Identification
Optimisation
• genomics
• transgenics
bioinformatics
• protein for
HTS
structural
chemistry,
DMPK
• transgenic
disease
models
cheminformatics
Concept
Testing
• genomics
• genetic
preselection
clinical informatics
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AZ continues finding the unique targets
• Major unmet
medical need
HCI
• Key functional relation
Parietal Cell
to pathophysiology
• Drugable
• Selective location
Proton
pump
Receptors
omeprazole
(Prilosec®)
Losec®
Nexium®
RAPID
Gastrin Histamine
Acetylcholine
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AZ exploitation of the genomic revolution
• Great opportunities to understand disease
mechanisms and to identify new drug
targets
• Maximise internal activities with exploitation
of genome collaborations
– Incyte, Affymetrix, Procardis/Oxagen,
MAN
• Genomics information widely deployed to AZ
MOUSE
SNP consortium etc.
– Focus on building Target Validation strengths
bioscientists via e-lab
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Exploiting AZ Bioinformatics e-lab
Pathway analysis
The key to
• Target validation and
pathway analysis
• Genome annotation
and mining
• Protein classification
User-friendly access
and capturing value from
complex databases
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Balancing the risk in drug discovery
Proportion of drug discovery effort
Kinase
Difficult <25%
(Protein - protein)
Drugable >75%
(GPCR, kinases
proteases, Nuclear R)
Undesirable
<5%
GPCR
(Cytokine R,
GF-R)
Do-ability of Target Classes
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AZ sources of chemical leads
Chemical
diversity
Best in class
Known
compounds
(patents)
Natural
ligands
Natural
products
AZ
compound
collection
(>1,000,000)
HighThroughput
Screening
(HTS)
Directed
libraries
Increasing
success
Rational design
(structure-led)
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Sophisticated cell function analysis by HTS
• High content screening
• Cellular events in real-time
• Simplified, but sophisticated
fluorescence methods
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AZ natural product screening and isolation
Unique diverse extract library
• Many of top pharmaceuticals have natural product origin
• Exceptional chemical diversity - meet target explosion
• Unique Australian collection of rainforest plants, marine
organisms, fungi, venoms etc.
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Rational structure-based design
An AstraZeneca strength
Internal and external
X-ray centres
Integrated
protein supply
Access to synchrotrons
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AZ exploitation of structural chemistry
X-ray crystallography
Melagatran in active site of thrombin
NMR
PPAR ligand binding
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Exploiting AZ Cheminformatics
• Compound collection
AstraZeneca
Global HTS
analysis and
enhancement
Charnwood
• High-Throughput
Alderley Park
Wilmington
Mölndal
Screening enhancement
• Structure-based design
• DMPK
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AZ ‘Integrative Pharmacology’
• Differentiating AZ strength
• Allows complete
biosystem
analysis: target validation,
safety, efficacy, DMPK,
surrogate markers
• Ensure clinical success
Patients
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Future ‘Integrative Pharmacology’
• Availability of human and mouse genome
and AZ transgenic centre
• Mouse can easily be genetically modified
to mimic human disease
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Human genetic defects: obesity, Alzheimer’s,
arteriosclerosis
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Human target sequence: validation
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Novel models of DMPK and toxicology
• Mouse miniaturisation:
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Advantage
- less compound needed
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Challenge
- physiological recordings,
bioanalytical chemistry
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