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

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

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

A Proteins Antibodies Gene therapy Xenotransplantation Antisense Vaccines Natural products Low molecular weight synthetic drugs The ultimate challenge for life science - discover drugs/treatment paradigms to alleviate or cure human disease

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

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

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

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

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

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

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

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

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

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

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

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

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

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