Transcript strategic development

KnowTox, a FrancoHungarian collaborative
project relative to toxicity
CONFIDENTIAL INFORMATION
Overview
 Aureus Pharma System
 ChemAxon and Aureus Relationships
 KnowTox project regarding druginduced hepatotoxicity
CONFIDENTIAL INFORMATION
The Aureus Pharma System
Knowledge Base
Integration Platform
Query Interface
Analysis/Display
Applications
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Aureus & ChemAxon
Business partnership
Integration of ChemAxon’s tools into our
system
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Cheminformatic tools
integrated in AurQUEST
CONFIDENTIAL INFORMATION
Aureus & ChemAxon
Business partnership
Integration of ChemAxon’s tools into our
system
Aureus Research and innovation
Projects
Communication and Dissemination
CONFIDENTIAL INFORMATION
Virtual Screening Study to Identify New T-type Calcium
Channel Blockers
Aureus
Database
Diversity
DB
AurQuest
(Biological Activity)
Representation & Chemical Space
Molecular descriptors & Fingerprints
N
O
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O
O
O
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O
N
N
N
N
O
(I)
H
N
O
N
N
(I)
O
N
O
H
N
N
N
Virtual Screening
Pharmacophoric Similarity
O
N
N
N
N
N
N
O
45 Query
structures
314 Hits
Compounds Selection :
1. Molecular diversity and chemical originality
2. Compounds availability
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38 compounds
ordered for testing
Preliminary electrophysiology
results
A
Peak current inhibition (%)
100
75
50
25
0
1 2 3 4 5 6
7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38
Compound #
B
C
Comp #14
Comp #3
0
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(pA)
(pA)
0
Internal projects
Instant JChem
Screen
JKlustor
LibMCS (being tested)
Fragmenter (use in near future)
CONFIDENTIAL INFORMATION
Aureus & ChemAxon
 Business partnership
Integration of ChemAxon’s tools into our system
 Aureus Research and innovation Projects
Communication and Dissemination
 Collaborative Eureka project :
Knowtox
CONFIDENTIAL INFORMATION
Drug-induced toxicity
1991 2000
45
% of all advanced molecules (n=88)
Chem. Res. Toxicol. 2007, 20: 344-369.
Sites for Toxicology Attrition
Attrition (%)
Nature Reviews Drug Discovery 2004, 3: 711-715.
40
35
30
25
20
15
10
5
30
25
0
20
15
10
5
0
Predicting drug toxicity
Target organ or tissue
Drugs withdrawn recently for hepatotoxicity
- Bioactivation alerts
- Knowledge of toxicity pathways
- Bromfenac  reactive metabolite
- Troglitazone  reactive metabolite
- Nefazodone  reactive metabolite
- Pemoline
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
PREDICTING SUITABILITY, SAFETY AND EFFICACY OF THERAPIES.
HEALTH-2007-1.3-1: Novel alternative testing strategies for use in pharmaceutical discovery and
development.
HEALTH-2007-1.3-2: Bottlenecks in reduction, refinement and replacement of animal testing in
pharmaceutical discovery and development.
HEALTH-2007-1.3-3: Promotion, development, validation, acceptance and implementation of QSARs
(quantitative structure-activity relationship) for toxicology.
HEALTH-2007-1.3-4: Alternative testing strategies for the assessment of the toxicological profile of
nanoparticles used in medical diagnostics.
HEALTH-2007-1.3-5: In silico modelling for ADMET outcomes.
 Theme 6 – Environment
ENVIRONMENTAL TECHNOLOGIES: TECHNOLOGY ASSESSMENT, VERIFICATION AND TESTING
ENV-2007-3.3.1-1: In silico techniques for hazard-, safety-, and environmental risk-assessment.
ENV-2007-3.3.1-2: Defining of a long-term research strategy for the full replacement of animal tests
for repeat dose systemic toxicity.
 Joint Technology Initiative for Innovative Medicines
InnoMed PredTox (FP6)
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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
Partners and involvement
- sanofi-aventis
- Aureus Pharma
- ChemAxon/Univ. Budapest
• Help to define database
structure and content
• Validate it
Define and Design
database structure
Validate predictive
software tools
Identify pertinent literature
Build the
model
Provide datasets for
model building
Integrate
literature
Define data needed for
building the models
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Deliverables
 New knowledgebase focused on
hepatotoxicity
 Database structure suitable for
internal data management purpose
 Metabolism prediction module
 Toxicity prediction software
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KnowTox database 1st 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
51%
9%
1%
5%
2%
Cell behaviour
Flux
Induction
Enzymology
In vivo: Toxicokinetics
In vivo: Others
32%
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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?
…
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AurQUEST Query software characteristics
Ask a (chemical and / or
biological) question
Retrieve a list of
compounds
Retrieve biological
information
Retrieve detailed
protocols & links to
bibliographical sources
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Metabolizer characteristics
xenobiotics
Metabolizer
Reactor
Biotransformation library
Metabolites
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Toxicity prediction
xenobiotics
Metabolites
+ stability
Toxicity
data
Toxicity Calculator
Fragmenter
Evaluator
Predicted toxicity
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Calculator
Calculator
plugin
Calculator
plugin
plugin
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
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« KnowTox »
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