Dr Claes WilhelmssonExecutive Director Research & Development

Innovation and the life sciences

A

CureCure

Disease preventionDisease prevention

Stop disease progressionStop disease progression

Symptomatic treatmentSymptomatic treatment

Increasing safety and delivery convenienceIndividualised, coupled to diagnosis

Sci

enti

fic

chal

len

ges

Sci

enti

fic

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The challenges of new treatment paradigmsThe challenges of new treatment paradigms

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Disease Mechanism

Optimal Dose Optimal Delivery

Diagnostic

Right Patient

Target

Right Drug

The Ultimate Therapy: Prevention or CureThe Ultimate Therapy: Prevention or Cure

Tailored TreatmentTailored Treatment

Optimal Therapy

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1.1. Proteins

2.2. Antibodies

3.3. Gene therapy

4.4. Xenotransplantation

5.5. Antisense

6.6. Vaccines

7.7. Natural products

8.8. Low molecular weight synthetic drugs

““The ultimate challenge for life science - The ultimate challenge for life science - discover drugs/treatment paradigms to alleviate discover drugs/treatment paradigms to alleviate

or cure human disease”or cure human disease”

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MolecularBiology

Genetics

Patents

Toxicology/Safety Assessment

MedicinalChemistry

CommercialInput

Medicalinput Regulatory

ProcessR&D

Pharmaceutical &Analytical R&D

Drug metabolism- pharmacokinetics

- bioanalysis

PharmacologyBioscience

High ThroughputScreening

Target ProteinProduction

ProductProduct

Multi-disciplincary teamworking - our key to successMulti-disciplincary teamworking - our key to success

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Enabling Science & Technology (EST) integrationEnabling Science & Technology (EST) integration

screeningscreeningstructuralstructural

chemistrychemistryEST ChemistryEST Chemistry

• geneticsgenetics • genomicsgenomics

• transgenicstransgenics

• transgenic transgenic disease disease modelsmodels

• genomicsgenomics

• genetic genetic pre-pre-selectionselection

EST BiologyEST Biology

• protein forprotein forHTS HTS structuralstructuralchemistry,chemistry,DMPKDMPK

EST InformaticsEST Informatics bioinformaticsbioinformatics cheminformaticscheminformatics clinical informaticsclinical informatics

Compound Compound

Optimisation

ConceptTarget

Validation

Target

Identification IdentificationRAsRAsTesting

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AZ continues finding the unique targetsAZ continues finding the unique targets

• Major unmet medical need

• Key functional relation to pathophysiology

• Drugable

• Selective locationProton pump

HCI

Receptors

Gastrin Histamine Acetylcholine

omeprazole(Prilosec®)

Losec®

Nexium®

RAPID

Parietal Cell

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• Great opportunities to understand disease mechanisms and to identify new drug targets

• Maximise internal activities with exploitation of genome collaborations

– Incyte, Affymetrix, Procardis/Oxagen, SNP consortium etc.

– Focus on building Target Validation strengths

• Genomics information widely deployed to AZ bioscientists via e-lab

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US

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MA

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AZ exploitation of the genomic revolutionAZ exploitation of the genomic revolution

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User-friendly accessand capturing value from complex databases

Exploiting AZ Bioinformatics e-labExploiting AZ Bioinformatics e-lab

Pathway analysis

• Genome annotation and mining

• Protein classification

• Target validation and pathway analysis

The key to

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Undesirable <5%(Cytokine R,GF-R)

GPCR

Kinase

Drugable >75%(GPCR, kinasesproteases, Nuclear R)

Difficult <25%(Protein - protein)

Do-ability of Target Classes

Pro

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rtio

n o

f d

rug

dis

cove

ry e

ffo

rtBalancing the risk in drug discoveryBalancing the risk in drug discovery

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High-Throughput Screening

(HTS)

AZcompound collection

(>1,000,000)

Natural products

Chemicaldiversity

AZ sources of chemical leadsAZ sources of chemical leads

Rational design (structure-led)

Natural ligands

Best in class

Known compounds

(patents)

Increasing success

Directed libraries

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Sophisticated cell function analysis by HTSSophisticated cell function analysis by HTS

• High content screening

• Cellular events in real-time

• Simplified, but sophisticated fluorescence methods

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• 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.

Unique diverse extract libraryUnique diverse extract library

AZ natural product screening and isolationAZ natural product screening and isolation

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An AstraZeneca strengthAn AstraZeneca strength

Rational structure-based designRational structure-based design

Access to synchrotronsAccess to synchrotronsIntegrated Integrated protein supplyprotein supply

Internal and externalInternal and externalX-ray centresX-ray centres

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AZ exploitation of structural chemistryAZ exploitation of structural chemistry

Melagatran in active site of thrombin

X-ray crystallographyX-ray crystallography

PPAR ligand binding

NMRNMR

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Exploiting AZ CheminformaticsExploiting AZ Cheminformatics

• Compound collection analysis and enhancement

• High-ThroughputScreening enhancement

• Structure-based design

• DMPK

Wilmington

Charnwood

AstraZenecaAstraZenecaGlobal HTSGlobal HTS

Mölndal

Alderley Park

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AZ ‘Integrative Pharmacology’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’Future ‘Integrative Pharmacology’

• Availability of human and mouse genome and AZ transgenic centre

• Mouse can easily be genetically modified to mimic human disease

– Human genetic defects: obesity, Alzheimer’s,arteriosclerosis

– Human target sequence: validation

– Novel models of DMPK and toxicology

• Mouse miniaturisation:

– Advantage - less compound needed

– Challenge - physiological recordings, bioanalytical chemistry