1. Dr Claes Wilhelmsson Executive Director Research & Development Innovation and the life sciences

2. A Cure Disease prevention Stop disease progression Symptomatic treatment Increasing safety and delivery convenience Individualised, coupled to diagnosis Scientific challenges The challenges of new treatment paradigms

3. A Disease Mechanism Optimal Dose Optimal Delivery Diagnostic Right Patient Target Right Drug The Ultimate Therapy: Prevention or Cure Tailored Treatment Optimal Therapy

4. A 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 - discover drugs/treatment paradigms to alleviate or cure human disease

5. A Molecular Biology Genetics Patents Toxicology/ Safety Assessment Medicinal Chemistry Commercial Input Medical input Regulatory Process R&D Pharmaceutical & Analytical R&D Drug metabolism - pharmacokinetics - bioanalysis Pharmacology Bioscience High Throughput Screening Target Protein Production Product Multi-disciplincary teamworking - our key to success

6. A Enabling Science & Technology (EST) integration screening structural chemistry EST Chemistry genetics genetics genomicsgenomics transgenicstransgenics transgenic disease modelstransgenic disease models genomicsgenomics genetic pre- selectiongenetic pre- selection EST Biology protein for HTS structural chemistry, DMPKprotein for HTS structural chemistry, DMPK EST Informatics bioinformaticscheminformatics clinical informatics Compound Optimisation Concept Target Validation Target Identification RAs Testing

7. A AZ continues finding the unique targets Major unmet medical need Key functional relation to pathophysiology Drugable Selective location Proton pump HCI Receptors GastrinHistamineAcetylcholine omeprazole (Prilosec ® ) Losec ® Nexium ® RAPID Parietal Cell

8. A 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 MOUSE MAN AZ exploitation of the genomic revolution

9. A User-friendly access and capturing value from complex databases Exploiting AZ Bioinformatics e-lab Pathway analysis Genome annotation and mining Protein classification Target validation and pathway analysis The key to

10. A Undesirable <5% (Cytokine R, GF-R) GPCR Kinase Drugable >75% (GPCR, kinases proteases, Nuclear R) Difficult <25% (Protein - protein) Do-ability of Target Classes Proportion of drug discovery effort Balancing the risk in drug discovery

11. A High- Throughput Screening (HTS) AZ compound collection (>1,000,000) Natural products Chemical diversity AZ sources of chemical leads Rational design (structure-led) Natural ligands Best in class Known compounds (patents) Increasing success Directed libraries

12. A Sophisticated cell function analysis by HTS High content screening Cellular events in real-time Simplified, but sophisticated fluorescence methods

13. A 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 library AZ natural product screening and isolation

14. A An AstraZeneca strength Rational structure-based design Access to synchrotrons Integrated protein supply Internal and external X-ray centres

15. A AZ exploitation of structural chemistry Melagatran in active site of thrombin X-ray crystallography PPAR ligand bindingNMR

16. A Exploiting AZ Cheminformatics Compound collection analysis and enhancement High-Throughput Screening enhancement Structure-based design DMPK Wilmington Charnwood AstraZeneca Global HTS Mölndal Alderley Park

17. A AZ Integrative Pharmacology Differentiating AZ strength Allows complete biosystem analysis: target validation, safety, efficacy, DMPK, surrogate markers Ensure clinical success Patients

18. A 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, Alzheimers, arteriosclerosis –Human target sequence: validation –Novel models of DMPK and toxicology Mouse miniaturisation: – Advantage- less compound needed – Challenge- physiological recordings, bioanalytical chemistry