CONFIDENTIAL INFORMATION KnowTox, a Franco- Hungarian collaborative project relative to toxicity

CONFIDENTIAL INFORMATION Overview Aureus Pharma System ChemAxon and Aureus Relationships KnowTox project regarding drug- induced hepatotoxicity

CONFIDENTIAL INFORMATION Knowledge Base Integration Platform Query Interface Analysis/Display Applications The Aureus Pharma System

CONFIDENTIAL INFORMATION Aureus & ChemAxon Business partnership Business partnership Integration of ChemAxons tools into our system

CONFIDENTIAL INFORMATION Cheminformatic tools integrated in AurQUEST

CONFIDENTIAL INFORMATION Aureus & ChemAxon Business partnership Business partnership Integration of ChemAxons tools into our system Aureus Research and innovation Projects Aureus Research and innovation Projects Communication and Dissemination

CONFIDENTIAL INFORMATION Aureus Database Representation & Chemical Space Molecular descriptors & Fingerprints Virtual Screening Pharmacophoric Similarity 314 Hits AurQuest (Biological Activity) DiversityDB 45 Query structures Compounds Selection : 1. Molecular diversity and chemical originality 2. Compounds availability 38 compounds ordered for testing Virtual Screening Study to Identify New T-type Calcium Channel Blockers

CONFIDENTIAL INFORMATION Preliminary electrophysiology results

CONFIDENTIAL INFORMATION Internal projects Instant JChem Screen JKlustor LibMCS (being tested) Fragmenter (use in near future)

CONFIDENTIAL INFORMATION Aureus & ChemAxon Business partnership Business partnership Integration of ChemAxons tools into our system Aureus Research and innovation Projects Aureus Research and innovation Projects Communication and Dissemination Collaborative Eureka project : Collaborative Eureka project : Knowtox

CONFIDENTIAL INFORMATION Drug-induced toxicity Clinical safety Efficacy Formulation PK/Bioavailability Commercial Toxicology Cost of goods Unknown/other Attrition (%) Nature Reviews Drug Discovery 2004, 3: Chem. Res. Toxicol. 2007, 20: Drugs withdrawn recently for hepatotoxicity - Bromfenac reactive metabolite - Troglitazone reactive metabolite - Nefazodone reactive metabolite - Pemoline Predicting drug toxicity - Bioactivation alerts - Knowledge of toxicity pathways

CONFIDENTIAL INFORMATION Predictive Toxicology European REACH (Registration, Evaluation, and Authorization of Chemicals) system Alternative methods predictive tools in toxicology Collection of high-quality data European work programme FP7 Theme 1 - Health Theme 6 – Environment Joint Technology Initiative for Innovative Medicines InnoMed PredTox (FP6) PREDICTING SUITABILITY, SAFETY AND EFFICACY OF THERAPIES. HEALTH : Novel alternative testing strategies for use in pharmaceutical discovery and development. HEALTH : Bottlenecks in reduction, refinement and replacement of animal testing in pharmaceutical discovery and development. HEALTH : Promotion, development, validation, acceptance and implementation of QSARs (quantitative structure-activity relationship) for toxicology. HEALTH : Alternative testing strategies for the assessment of the toxicological profile of nanoparticles used in medical diagnostics. HEALTH : In silico modelling for ADMET outcomes. ENVIRONMENTAL TECHNOLOGIES: TECHNOLOGY ASSESSMENT, VERIFICATION AND TESTING ENV : In silico techniques for hazard-, safety-, and environmental risk-assessment. ENV : Defining of a long-term research strategy for the full replacement of animal tests for repeat dose systemic toxicity.

CONFIDENTIAL INFORMATION Global Project Knowledge base on drug-induced hepatotoxicity mined from literature Chemical and biological liver toxicity information for reference compounds associated with ADME properties Preclinical and clinical studies Query software tool for efficient data mining and exploitation Software tools for predicting metabolism and toxicity Metabolite prediction Metabolic stability prediction Hepatotoxicity prediction

CONFIDENTIAL INFORMATION Define and Design database structure Integrate literature Provide datasets for model building Define data needed for building the models Identify pertinent literature Build the model Help to define database structure and content Validate it Validate predictive software tools - sanofi-aventis - Aureus Pharma - ChemAxon/Univ. Budapest Partners and involvement

CONFIDENTIAL INFORMATION Deliverables New knowledgebase focused on hepatotoxicity Database structure suitable for internal data management purpose Metabolism prediction module Toxicity prediction software

CONFIDENTIAL INFORMATION KnowTox database 1 st version Molecules tested as or reported as hepatoxicants Biological quantitative / qualitative in vitro or in vivo activity Biological protocol description and details Bibliographical sources Links to external resources

CONFIDENTIAL INFORMATION Typical Queries 1. What are similar compounds to my potential hepatoxicant in term of given hepatotoxic biomarkers? 2. What are toxicological information regarding a particular chemical substructure or therapeutic class? 3. What are the histological endpoints of compounds of interest? 4. What type of cellular dysfunction injury has been described for compounds of interest? …

CONFIDENTIAL INFORMATION Ask a (chemical and / or biological) question Retrieve biological information AurQUEST Query software characteristics Retrieve a list of compounds Retrieve detailed protocols & links to bibliographical sources

CONFIDENTIAL INFORMATION Metabolizer characteristics Metabolizer ReactorBiotransformation library xenobiotics Metabolites

CONFIDENTIAL INFORMATION Toxicity prediction Toxicity Calculator FragmenterEvaluator Calculator plugin Calculator plugin Calculator plugin xenobiotics Metabolites + stability Toxicity data Predicted toxicity

CONFIDENTIAL INFORMATION KnowTox Added-Value Complete package for integration in drug discovery process Quick search and retrieval of information Improved efficiency to manage such undesirable events Better risk assessment (management and anticipation) Impact on probability of success to market new drugs

CONFIDENTIAL INFORMATION Acknowledgments Miklos Vargyas György Pirok Ferenc Csizmadia György Horvai Gilles Labbe Emmanuela Aly Frédéric Galli François Petitet Ismaïl Ijjaali KM & IT teams

CONFIDENTIAL INFORMATION « KnowTox »