Collaboration public privé Jean-Luc GALZI
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Collaboration public privé
Jean-Luc GALZI Marie-Louise JUNG
Fondation maladies Rares, 7 mai 2019
Small molecules to understand living systems and treat diseases
Small molecules to understand living systems and treat diseases
Chemo- Chemical
informatics libraries
Advice and
project
management
Screening ADME-Tox
https://chembiofrance.cn.cnrs.fr/fr/
The National Chemical library
45 academic laboratories (shareholders)
Compounds gathered: 73397
Compounds in plates: 54166
Natural extracts: 15116
Iso 9000 Certification
One unique distribution Center in Toulouse (GLP)
• Collect new compounds
• Distribute molecules
• Quality control (MS)
• Maintain database (FAIR)
• Re-synthetize hit molecules
• Train users and librarians
http://chimiotheque-nationale.cn.cnrs.fr/?lang=en
Notable features of
the National
Design of sub-libraries
Chemical No - Essential collection
Library commercial - Focused libraries
compound ✔ - On demand (cherry picking) ✔
Collaboration with chemists ✔
for hit re-synthesis, analogs
design and synthesis, drug
development
specificities
Integration to other pillars
of the infrastructure ✔
(chemoinformatics,
ADMET …)
Chemoinformatics network
Virtual ü ligand-based
Screenings ü structure-based A network of 8 sites :
ü CN subset
Libraries
ü approved drugs
Design ü commercial cpds
PPI QSAR,QSPR
ADMET
Raw data ü PAINS/reacBvity alert Virtual screening/
analysis ü analogs in catalogs Membrane proteins
and ü properBes predicBon Library design
SAR building LogP, Sol.,Kd, Kon/Koff
ü prioritizing cpds
Synthesis ü prioritizing reagents
ü scaffold hopping
Kinases / Nucl R QSAR
Bio-Profiling
ü Metabolism (site, CYP450s…)
& ADME-Tox ü Off-targets PPI
PredicBon
https://www.ibisa.net/plateformes/detail.php?tri=Criblage%20et%20chimioth%E8que&srch=&q=586
A network of screening centers
Screening = Binding + Function HCS
Soluble target - Cell metabolism (proliferation, Kinases
Fluorescence apoptosis, nécrosis, mitosis, Cancer Target-based
polarization, alpha- autophagy, autophagy,
screen, TRF, Membrane potential)
radioactivity - Gene expression (Reporter
gene expression, chemokines, Natural
Membrane proteins cytokines, etc) substances
FRET, HTRF - Migration (chemotaxis, Wound
healing)
Label free methods - Morphology (Intracellular Phenotypic screens
(DMR etc..) trafficking, cytoskeleton)
- Signalling (cAMP, IP1, calcium,
Biomarker detection and GPCRs
quantification …)
- Microbiology (viral replication,
Emerging diseases/
NMR/ microbiology
bacterial proliferation)
Fragment-based
A network of ADMET centers
Three pla)orms :
- Physicochemistry
(solub; LogP/D; pKa; Chemical stab;
plasma stab; prot binding …)
- AbsorpCon (vitro/vivo)
(caco2; PAMPA; p.o.; i.v.; cut; i.p., i.n. …) Labeling of
molecules
- DistribuCon (vivo)
(all Cssues)
- Metabolism (vitro / vivo)
(metab stab; recombinant CYP;
microsomes; primary & secondary
metabolites; metabolite id)
- PharmacokineCc (vivo)
(8 routes of administraCon; brain)
Achievements (2007-2017)
Published articles 1450
theses 500
training 1000
users >1000
Number of screens 385
Patents / active licences 84 / 35
BioTools identified 65 (database under construction)
Laboratories of excellence 2 (20M€ funding for probe discovery)
Start-up created 7 Cellipse, Biokinesis, Ecrins therapeutics,
Abivax, Biodol, Therapeutics, Quiid, aptaeus,
Manros Therap
Associated companies Prestwick Chemical (Strasbg), Domain
Therapeutics (Strasbg), Bioversys (Lille)
Aknowledgements • Dr Florence MAHUTEAU, Pr. Pascal BONNET, Heads of chemical library • Dr. Didier ROGNAN, Dr. Dominique DOUGUET Heads of chemoinformatics • Dr. Pascal VILLA, Dr. M-Odile FAUVARQUE, Heads of Screening platforms • Dr. Pascal VILLA Head of ADME-T
Prestwick Chemical: What Do We Offer?
• Prestwick Chemical Library ®
• Prestwick CNS and GPCR Library
• Prestwick Drug Fragment Library • Hit Discovery
• Prestwick Phytochemical Library • Post HTS Services
• Prestwick Peptidic Macrocycle Library • MedChem Projects
• Prestwick Original Molecules • Chemistry Services
• Prestwick Frag-to-lead Library (2019) • Computational Services
• Analytical ServicesThe Prestwick Chemical Library ®
1280 small molecules: Royalty-free “no strings attached” compounds
95% FDA-EMA approved drugs - marketed off-patent
Since 2000
Regularly updated, new update in July 2019, up to 1520 compounds
Designed to increase potential “high –quality” hits
Compounds selected for:
○ high chemical diversity
○ high pharmacological diversity
○ known bioavailability
○ safety in humansThe Prestwick Chemical Library ®
Used for :
o Assay validation
o Start of new optimization process
o Finding of stem cell growth modulators
o Repurposing/ repositioning
o …….Highly annotated database
The Prestwick Chemical Library ® FACTS o High quality Library, each compound checked for identity & purity (powder stock and DMSO) o Mentioned in > 400 publications worldwide, around 20 on Rare Diseases projects o Tested on Rare Diseases platforms: 14 x at PCBIS + 1 project ongoing and several other platforms (Lille, Grenoble, Saclay, Toulouse, …) o Direct Repositioning is possible (Ann. Neurol 2018: 84:260 – Acute Ischemic stroke) o Drug-drug combination will allow new IP issues (ex anti-inflammatory + a drug)
Neutraligands de Chimiokines
Criblage « target-based » Applications : Inflammations – douleur, asthme, dermatites, WHIM, cancer, etc.
Porteurs : J-L Galzi, N Frossard, M Hibert, D Bonnet
UMR7200 - UMR 7242 Strasbourg
Chimiothèques criblées :
• Chimiothèque Nale : 6000 composés
• Prestwick : 1200 composés
2009 : Criblage moléculaire (FRET)
2010 : Nouveau concept – Neutraligand -> orphan drug designation
2010-2017 : hit to lead, prodrug, antedrug
2010-2018 : Efficacité in vivo sur modèles d’inflammation, de
douleur, asthme, dermatite, lupus, WHIM, etc.
• PK / Imagerie
2017 : Brevet
Maturation SATT Conectus – Recherche de partenaire industriel
Brevet : 2017, extension 2018
Publis :
- Neutralizing endogenous chemokines with small molecules. Principles and potential therapeutic applications. Hachet-Haas M. et al. Pharmacol Therapeut 2010, 126, 39-55.
- Prodrugs of a CXC Chemokine-12 (CXCL12) Neutraligand Prevent Inflammatory Reactions in an Asthma Model in Vivo Gasparik V et al. ACS Med Chem Lett 2012, 3, 10-14
- An antedrug of the CXCL12 neutraligand blocks experimental allergic asthma without systemic effect in mice. Daubeuf F. et al. J Biol Chem. 2013 288(17):11865-76.
- A strategy to discover decoy chemokine ligands with an anti-inflammatory activity. Abboud D. et al. Sci Rep. 2015 Oct 7;5:14746.Correction des mutations non sens
Criblage phénotypique Proposer des approches thérapeutiques pour les maladies génétiques causées par des mutations non sens
Porteur : Fabrice Lejeune
Équipes : UMR 8161 (IBL – Lille)
UMR 7245 (MNHN - Paris)
Chimiothèques criblées :
• Prestwick (1200 composés )
• CNE (640 composés)
• Extractothèque Nale (20.000 extraits) Lepista flaccida
2012… : Criblage, validaUon sur lignées cellulaires, cellules
de paUents et in vivo dans des modèles murins, mesure de
la concentraUon efficace et déterminaUon du mode d'acUon
détermination du composé actif de l'extrait et test de
molécules dérivées (mucoviscidose)
Maturation en cours…
Brevet français déposé en 2016 et international en 2017
Publication : H Benhabiles, S Gonzalez-Hilarion, S Amand, C Bailly, A Prévotat, P Reix, D Hubert, E Adriaenssens, S
Rebuffat, D Tulasne, F Lejeune Optimized approach for the identification of highly efficient correctors of nonsense
mutations in human diseases PLOS ONE 2017.Other Screening Libraries
o Prestwick CNS Library : subset of 320 drugs meeting BBB penetration criteria
o Prestwick GPCR Library: subset of 270 drugs dedicated to GPCR research
o Prestwick Phytochemical Library : selection of 320 pure natural compounds
o Prestwick Fragment Library: extended to 1464 fragments coming from smart fragmentation of marketed drugs
o Prestwick Original Molecules Library: a set of 344 exclusive compounds – provided for being tested at PCBIS
o Prestwick Macrocyclic Peptide Library: a set of 400 short macrocycles
o Prestwick Frag-to-lead Library: a set of 400 arising from combination of fragments from approved drugs
o Focused and customized Libraries: for a broader offer
18Post HTS Services
Hit Confirmation: hit re–resupply, hit analysis, hit analogs procurement
Includes:
o Selection of hit series (1-5)
o Search and selection of structural analogues within the available chemical space (10Mo compounds)
Deliverable:
10 to 50 QCed analogues
Overall Duration: 1-3 months
Hit / Series Validation: design and synthesis of new analogues
Includes:
o SAR-driven design with IP consideration and chemical traceability
o Iterative cycles including design/synthesis of analogues and activity testing
o Early ADME/Tox characterization for selection WITH PCBIS/TECHMEDILL
Deliverable:
15 to 40 analogues
Overall Duration: 3-4 months
Aim: confirm biological activity for 1 or 2 chemical series possibly entering Hit to Lead phasesPost HTS Services
Hit to Lead
Selection in a multidisciplinary environment of the most promising scaffold
Allows to get a compound towards POC in an animal model
Includes:
o Multiparameter optimization of 1 or 2 chemical series (e.g. activity, selectivity, early ADME profile)
o Iterative cycles including design/synthesis and activity testing
o IP landscape will be considered for the design
o Bi-weekly reports
Deliverable:
o 80-120 compounds (20 mg)
o Lead compound
Overall Duration: 8-12 monthsThank you!
Marie-Louise Jung, Pharm D., PhD.
Prestwick Chemical VP Sales Business Development
Europe, Asia, Australia
Email: marielouise.jung@prestwickchemical.fr
www.prestwickchemical.com
Boulevard Gonthier d’Andernach
Parc d’Innovation,
67400 ILLKIRCH – STRASBOURG
FranceStimulators of Interferon Genes
Criblage phénotypique Stimulateurs de la réponse immunitaire innée & antiviraux à large spectre
Chimiothèque criblée :
• Chimiothèque Nale (~25.900 composés)
Porteur : Pierre-Olivier Vidalain (UMR 3569, Paris) • Prestwick (1200 composés)
• Chemical Diversity (~ 14000 composés)
• Chem-X-Infinity (10000 composés)
è ~ 50 hits
2008-2010 : criblage cellulaire inducteurs de la
réponse interféron
2011 : criblage cellulaire inhibiteurs du virus de
ISRE luciferase
la rougeole (interferon inducible antiviral genes)
2013 : identification de la cible (voie de
biosynthèse des pyrimidine: DHODH)
2009-2015 : validation des hits - études
structure/activité – études ADME-Tox
Luciférase
2016… : maturaion en cours sur
d’autres applicaions thérapeuiques
2 brevets (2010 et 2014)
10 publis :
• Lucas-Hourani M, Dauzonne D, Jorda P, Cousin G, Lupan A, Helynck O, Caignard G, Janvier G, André-Leroux G, Khiar S, Escriou N, Desprès P,
Jacob Y, Munier-Lehmann H, Tangy F, Vidalain PO. PLoS Pathog. 2013;9(10):e1003678.
• Munier-Lehmann H, Lucas-Hourani M, Guillou S, Helynck O, Zanghi G, Noel A, Tangy F, Vidalain PO, Janin YL. J Med Chem. 2015;58(2):860-77.
• Lucas-Hourani M, Dauzonne D, Munier-Lehmann H, Khiar S, Nisole S, Dairou J, Helynck O, Afonso PV, Tangy F, Vidalain PO. Antimicrob Agents
Chemother. 2017;61(10).The chemical biology academic initiative in France
A vision:
From gene to function
From function to gene
A mission:
Discover Small molecules (Biotools) to understand living
systems
An infrastructure with four pillars : ChemBioFrance
- The National Chemical Library
- A chemoinformatics network
- A screening platforms network
- An ADME-T platforms networkYou can also read
