Docstoc

05_Joossens_ADDN_UA

Document Sample
05_Joossens_ADDN_UA Powered By Docstoc
					The Antwerp Drug Discovery
Network
A Medicinal Chemistry, Biochemistry and Biology Platform



Dr. Jurgen Joossens, PhD, Pharm. D.
Project Manager ADDN




                                      Antwerp Drug Discovery Network
The Antwerp Drug Discovery
         Network




                                               2
              Antwerp Drug Discovery Network
                 Medicinal Chemistry @ UA
Personnel:                  Enzyme inhibitors
   •   Staff: 4             Disease areas: Endocrinology, Neurology, Cancer,
                            Infectious Diseases,…
   •   PostDoc: 8
                            Targets: Serine and cysteine proteases, nucleoside hydrolases,
   •   PhD students: 4      …
   •   Technical Staff: 1   Design, Synthesis and Evaluation
                            Hit to lead and lead optimization projects
                            Probe design to study in vivo off-target and on target
                            effects
                            Probe design for biomarker studies (near future)
                            Multiple collaborations with industrial partners


                                                              Equipment for organic
Plans for Near Future                                         chemistry
Relocation to a new building (2009)                                NMR, LC-MS, HPLC…
     Space for about 20 chemists                              Molecular modeling
second NMR (approved)                                              MOE software suite
Implementation of ADME evaluation (ongoing)                   Electronic Laboratory
                                                              Notebook (ELN)




                                                                                         3
                                                Antwerp Drug Discovery Network
                 Compounds and Results
                                             DPP Inhibitors
                                             -Pioneers in design of DPP IV
                                             inhibitors
                                             -The first potent and selective DPPII
                                             inhibitor with oral bioavailability
                                             -The first irreversible DDP 8 inhibitor

Potent and Selective uPA inhibitors
-   Considerable significant Metastasis
    reduction
      • Number of lung foci
      • Weight of axillary lymph nodes
-   Dose dependent
-   UAMC-00251, 1 mg/kg
      • 70 and 73% reduction of metastasis
-   No acute Toxicity



                                    Multiple Patent Applications
                                                                                       4
                                                Antwerp Drug Discovery Network
                                     LMPH

Personnel:                  Biological evaluation of drug like compounds
   •   Staff: 3             Disease areas: Bacterial, Fungal and Parasitic infections
                            Model Development (in vitro + in vivo)
   •   PostDoc: 1
                            Biofilms
   •   PhD students: 8
                            HTS-screening (WHO +DNDi screening center)
   •   Technical Staff: 7   Multiple collaborations with industrial partners



 Plans for Near Future
 Implementation of ADME evaluation (ongoing)
 Electronic Lab notebook system is installed




                Methods:
                Microbiology and cell culture techniques (biosafety cabinets)
                Animal models for infectious diseases (BSL-2)
                Flow cytometry for studying apoptosis, e.a.
                EPR and microscopic imaging techniques for mode-of action studies
                Biofilm laboratory models


                                                                                        5
                                               Antwerp Drug Discovery Network
              Current research topics

• Study of the intestinal mucosal response and oxidative stress on
  the course of Giardia duodenalis infection
• Molecular markers for epidemiological monitoring of drug
  resistance in visceral leishmaniasis
• Mode-of-action, pharmacodynamics and toxicity of a triterpene
  saponin PX-6518, a potent new lead structure with selective
  antileishmania activity
• Evaluation of biocides against bacterial biofilms
• Adhesion mechanisms of Helicobacter pylori as potential target
  for novel therapies.
• EU 7th FP: KALADRUG: New tools for monitoring drug
  resistance and treatment reponse in Visceral Leishmaniasis in
  the Indian subcontinent 01/10/2008-31/12/2012




                                                                     6
                                    Antwerp Drug Discovery Network
                    Medical Biochemistry
Personnel:

-   Staff: 4                  Biochemical Evaluation
-   PostDoc: 1                Proteolytic regulation of biological processes by
-   PhD students: 5           endopeptidases and exopeptidases in human:
-   Technical Staff: 3         Endocrinology, Neurology, Cancer, Infectious Diseases,…
                              Targets: DPPIV, DPPII, DPP8/9, uPA, CPU, CPM, POP/PEP
                              Isolation, expression, molecular characterization,
                              functional exploration in vitro and in vivo, effects of
                              inhibition, clinical and diagnostic applications,
                              therapeutic drug target discovery.
                              Multiple collaborations with industrial partners


Equipment
    Tecan microtiter spectrofluorometer, Shimadzu kinetic spectrofluorometer , Shimadzu
    continous flow spectrofluorometer, Molecular Devices Spectramax 340 + 190, Hewlett-
    Packard   diode-array spectrophotometer, Äkta explorer low pressure liquid
    chromatographic system , BioPilot protein preparative chromatographic station , Liquid
    chromatographic systems Pharmacia and Gilson , PCR system Perkin Elmer,…



                                                                                         7
                                               Antwerp Drug Discovery Network
                                                                                                                                      Results
                                                                                                                                                                             0.5
                      5

                                                                                                                                           UAMC-0038
                                                                                                                                                                                                                                   0.0024
                                                                                                                                                                                       A                                                        B
                      4                                 250 nM                   HO                                                                                          0.4                                                    0.002
                                                                                                 N
                                                                                             H                N

                                                                                                                                           binding to DPP8
                                                                                             N
                                                100 nM                                                                                                                                                                             0.0016
                      3                                                                               O




                                                                                                                                                                Absorbance
                                                                                                                                                                             0.3




                                                                                                                                                                                                                    k obs (s -1)
                                               25 nM
                      2                                                                  Vildagliptin (Galvus®)                                                                                                                    0.0012

                                          10 nM                                                                                                                              0.2

                      1                                                                                                                                                                                                            0.0008
                               0 nM
                                                                                                                                                                             0.1
                      0                                                                                                                                                                                                            0.0004




                                                                                                                                Substrate specificity of DPP4
                      5                                                                                           insulin
                                                                  250 nM
                                                                                             β cell                                                                           0                                                        0

                      4                                                                                                                                                            0       1200              2400                           0       2              4   6
                                                                 100 nM
                                                                                                          ⊕                                                                                       Time (s)                                              [I] (µM)
                      3                         10 nM             25 nM                          ⊕   GIP            Intestine


                                                                                                                                   In vitro pharmacology of proline specific
                      2
                                0 nM                                                  DPP4       GLP-1
                      1


                                                                                                                                   dipeptidyl peptidase inhibitors
                                                                                                   during
                      0
                          0               20                40            60
                                                                                                 food intake
                                               Time (min)




                      Prolyl oligopeptidase accelerates α-synuclein
                      aggregation in vitro
                          0,32

                                                  no inhibitor
                          0,28
Absorbance (350 nm)




                                                                           ZPP
                                                                                       UAMC-00021
                          0,24
                                                                                       no PO


                              0,2



                          0,16

                                                                                                                                    Expression of CPM and potential role in stem
                                      0           20             40        60      80
                                                                                 time (h)
                                                                                          100     120         140       160
                                                                                                                                    cell mobilisation


                                                                                                                                                                                                                                                                           8
                                                                                                                                                    Antwerp Drug Discovery Network
          Current research topics

• EU 7th FP: NEUROPRO: A.M. Lambeir –
  Oligopeptidase inhibitors in brain function and
  dysfunction: towards new therapeutic strategies for
  neuroprotection. 01/10/2008 - 30/09/2012
• Kinetic mechanism and substrate specificity of
  carboxypeptidase M
• Study of carboxypeptidase M expression in the kidney
• Study of dipeptidyl peptidases and inhibitors in
  ischemia-reperfusion injury
• Bacterial dipeptidyl peptidases as virulence factors



                                                               9
                              Antwerp Drug Discovery Network
           Why Collaborate With ADDN?

ADDN has a recognized experience in:         Laboratory of Microbiology,
                                             Parasitology and Hygiene (LMPH)
                                             Prof. Dr. Louis Maes
• screening for tropical diseases
                                             Groenenborgerlaan 171
• biochemical evaluation of peptidase        2020 Antwerp - Belgium
inhibitors                                   Tel.: +32 3 265 33 54
• lead design and lead discovery             louis.maes@ua.ac.be
                                             www.ua.ac.be/lmph
ADDN has experience with industrial          Laboratory of Medical Biochemistry
                                             Prof. Dr. Anne-Marie Lambeir
collaborations and researchers are used
                                             Universiteitsplein 1
to working under confidentiality             2610 Antwerp - Belgium
agreements                                   Tel. +32 3 820 27 27
ADDN wants to generate IP for itself and     anne-marie.lambeir@ua.ac.be
for its partners                             Laboratory of Medicinal Chemistry
ADDN also has an educational remit.          Prof. Dr. Koen Augustyns
                                             Laboratory for Medicinal Chemistry
Embedded in the University of Antwerp
                                             Universiteitsplein 1
we have access to excellent researchers      2610 Antwerp - Belgium
and teachers to prepare students for a       Tel. +32 3 820 27 03
carrier in the industry                      koen.augustyns@ua.ac.be
                                             www.ua.ac.be/medicinalchemistry


WWW.ADDN.BE
                                                                                  10
                                           Antwerp Drug Discovery Network

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:11
posted:9/14/2012
language:Unknown
pages:10