Insulin Degrading Enzyme modulators

Team

  • Team Leader: Pr Rebecca Deprez-Poulain PhD PharmD MRSC
  • Damien Bosc - Ass. Prof.
  • Paul Hermant - PhD student
  • Jouda Jakhlal - PostDoc
  • Julie Dumont - Ass Eng
  • Florence Leroux PhD -PharmD
  • Valerie Landry
  • Julie Dumont
  • Sandrine Dassonneville
  • Former team members
  • Gonzague Berte - PhD student
  • Damien Bosc PhD - Post-doc
  • Tristan Verdelet PhD -Post-doc
  • Jamal Elbakali PhD -Post-doc
  • Cyril Ronco PhD - Post-Doc
  • Xavier Marechal PhD - Post-doc

Mission

Explore the function of Insulin-Degrading-Enzyme (IDE) with small chemical modulating Ligands.

Approach

The objective of the project is to study the role of insulin-degrading enzyme (IDE) in cells and in normal and sick mice using small exosite modulators of IDE that modify the substrate binding pocket occupancy and the proteolytic profile of IDE. The project focuses on Type-II-diabetes and Alzheimer’s disease, two diseases where insulin and β-amyloid peptide, two cognate substrates of IDE, are involved. The data produced by the project will allow a better understanding of the (patho)-physiological role of IDE. The discovered modulators could eventually find applications in these pathologies. This project is tailored within the framework of 4 complementary teams: Medicinal chemistry / Chemical biology / ADME-PK (Déprez et al), Protein expression, crystallization and X-ray structure determination (Tang et al), Cell biology and vivo (van Endert et al) and Diabetes (Staels et al).

Latest results

Deprez’s team has a strong experience in the screening and optimization of modulators of Zinc-metalloproteases. In the course of the screening of a proprietary 2500-compound library on IDE using a labeled Aβ substrate, we identified a 5 µM inhibitor. The co-crystal structures revealed that very interestingly, our compounds bind to the exosite of IDE. Consistent with that observation, in vitro modulation of IDE in the presence of our compounds is variable depending on the substrate. Our compounds behave as either inhibitors or activators depending on the substrate. We also applied the concept of in situ Click-chemistry to IDE and obtained and optimized original inhibitors of this enzyme. Compounds have shown activity in vivo.

Deprez-Poulain, R., et al Catalytic site inhibition of IDE induces glucose intolerance in mice. Nature Comm., 2015, 6. doi:10.1038/ncomms9250 OPEN ACCESS

Deprez-Poulain, R. From In situ Click to in vivo pharmacology: Effect of catalytic site inhibition of Insulin Degrading Enzyme on glucose tolerance,51st International Conference on Medicinal Chemistry,Avignon, France,1st-3rd July 2015, Invited.

Publications

  • Bosc, D., Jakhlal, J., Deprez, B., & Deprez-Poulain, R. Kinetic target-guided synthesis in drug discovery and chemical biology: a comprehensive facts and figures survey. Future Medicinal Chemistry,2016: in press. doi:10.4155/fmc-2015-0007 OPEN ACCESS
  • Deprez-Poulain, R., Nathalie, H., Bosc, D., Liang, W. G., Enee, E., Marechal, X., Julie, C., Totobenazara, J., Berte, G., Jahklal, J., Verdelet, T., Dumont, J., Dassonneville, S., Woitrain, E., Gauriot, M., Paquet, C., Duplan, I., Hermant, P., Cantrelle, F.-X., Sevin, E., Culot, M., Landry, V., Herledan, A., Piveteau, C., Lippens, G., Florence, L., Tang, W. J., Van Endert, P., Staels, B., & Deprez, B. Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice. Nature Communications,2015, 6. doi:10.1038/ncomms9250 OPEN ACCESS
  • Charton, J., Gauriot, M., Totobenazara, J., Hennuyer, N., Dumont, J., Bosc, D., Marechal, X., Elbakali, J., Herledan, A., Wen, X., Ronco, C., Gras-Masse, H., Heninot, A., Pottiez, V., Landry, V., Staels, B., Liang, W. G., Leroux, F., Tang, W. J., Deprez, B., & Deprez-Poulain, R. Structure-activity relationships of Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, dual binders of human Insulin-Degrading Enzyme. Eur J Med Chem. 90: 547-567 doi:10.1016/j.ejmech.2014.12.005
  • Charton, J., Gauriot, M., Guo, Q., Hennuyer, N., Marechal, X., Dumont, J., Hamdane, M., Pottiez, V., Landry, V., Sperandio, O., Flipo, M., Buee, L., Staels, B., Leroux, F., Tang, W.-J., Deprez, B., & Deprez-Poulain, R. Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-b hydrolysis. European Journal of Medicinal Chemistry,2014, 79: 184-193.10.1016/j.ejmech.2014.04.009

Conferences

2016

  • Hermant, P. Plasma and Microsomal Esterases involvement in the Metabolism of Hydroxamic acids in two species,23rd Young Research Fellow Meeting of the SCT,Lille, France,15th-17th Feb. 2016, Flash presentation.

2015

  • Deprez-Poulain, R. From In situ Click to in vivo pharmacology: Effect of catalytic site inhibition of Insulin Degrading Enzyme on glucose tolerance,51st International Conference on Medicinal Chemistry,Avignon, France,1st-3rd July 2015, Invited
  • Hermant, P. Hydroxamates as bioactives molecules: ADME properties, inhibitors of ERAPs, Inhibitors of IDE,2nd F3 Meeting,Ghent, Belgium,24th Mar 2015,

2014

  • Deprez, B. Insulin Degrading Enzyme: deploying chemical concepts and tools to shed a new light on a highly conserved yet poorly understood protein.,Biocis,Chatenay Malabris, France,25th Sep. 2014, Invited.
  • Deprez, B., Deprez-Poulain, R., Willand, N., A., B., Leroux, F., Staels, B., Bosc, D., Ronco, C., & Villemagne, B. Structure-Based, Ligand Efficiency Driven Discovery and Early ADME, Learnings from two targets: EthR and Insulin Degrading Enzyme.,97th Canadian Chemistry Conference and Exhibition,Vancouver, Canada,1st-5th Jun 2014, Invited.
  • Deprez-Poulain, R. Hydroxamates as tools for the target validation of metalloproteases: Applications to malarial PfAM1 and human Insulin-Degrading Enzyme,National Centre for Scientific Research" Demokritos",Athens, Greece,30th October 2013, Invited.
  • Marechal, X., Bosc, D., Charton, J., Totobenazara, J., Berte, G., Verdelet, T., Dumont, J., Dassonneville, S., Gauriot, M., Paquet, C., Duplan, I., Herledan, A., Piveteau, C., Staels, B., Leroux, F., Hennuyer, N., Deprez, B., & Deprez-Poulain, R. Inhibition de la différenciation des myoblastes par des inhibiteurs de l’enzyme insulysine développés par click chemistry in situ.,Congrès SFBBM - GT Enzymes,Paris, France,4th-6th September 2013.
  • Deprez-Poulain, R., Berte, G., Bosc, D., Marechal, E., Gauriot, M., Hennuyer, N., Leroux, F., Charton, J., Lippens, G., Tang, W. J., Staels, B., & Deprez, B. X-ray Crystallography, Kinetic Target-guided synthesis and NMR to unravel the mode of action of insulin degrading enzyme modulators,NovAliX Conference,Strasbourg France,15th-18th October 2013.
  • Deprez-Poulain, R., Bosc, D., Leroux, F., Charton, J., Tang, W. J., & Deprez, B. Discovery and optimization of Insulin-Degrading Enzyme inhibitors by screening and target-guided synthesis: from structure to cellular activity.,17th RSC/SCI Medicinal Chemistry Symposium,Cambridge, UK,8th-11th September 2013.
  • Deprez-Poulain, R., Leroux, F., Piveteau, C., Charton, J., Dumont, J., Marechal, E., Bosc, D., Pottiez, V., Dassonneville, S., Hamdane, M., Hennuyer, N., Guo, Q., Liang, V., Tang, W. J., Staels, B., & Deprez, B. Modulators of Insulin Degrading Enzyme, from Structure to Function,Drug Discovery & Therapy World Congress 2013 Boston, USA ,3rd – 6th June 2013, Invited.
  • Bosc, D. Discovery via in situ click chemistry and structure activity relationships of inhibitors of Insulin-Degrading Enzyme.,Rencontres PRIM de la Chimie, de la Biologie et de la Physique,PRIM,28th May 2013, Lille, France.
  • Deprez-Poulain, R., Willand, N., Marechal, X., Bosc, D., Leroux, F., Charton, J., Villemagne, B., Wen, X., Elbakali, J., Berte, G., Tang, W. J., Baulard, A., Villeret, V., & Deprez, B. In situ protein-templated synthesis and fragment-based drug discovery, application to a bacterial transcriptional repressor and a human protease”,The 9th IUPAC International Symposium of Chemical Biology and 8th International Symposium,Beijing, China,25th-29th August 2012,Invited.
  • Deprez-Poulain, R., Charton, J., Willand, N., Tang, W. J., Baulard, A., Villeret, V., & Deprez, B. Structure-based design of receptor and enzyme modulators: Case studies in drug-discovery and  chemical biology.,BIT's 1st Annual International Conference of Medicinal Chemistry,Beijing, China,18-20 May 2010, Invited.
  • Deprez-Poulain, R. First substrate-dependant modulators of insulin degrading enzyme,Journée Commune SFC/SCT/ANP,Paris,23rd Mar 2010, Invited.
  • Totobenazara, J., Leroux, F., Landry, V., Tang, W. J., Deprez, B., Deprez-Poulain, R., & Charton, J. In situ click chemistry to discover IDE inhibitors,XVIIième Journée Jeunes Chercheurs SCT,Paris,5th February 2010, XVIIième Journée Jeunes Chercheurs SCT.

Poster communications

2016

  • Jakhlal, J., Hennuyer, N., Charton, J., Dumont, J., Dassonneville, S., Hermant, P., Bosc, D., Ronco, C., Leroux, F., Tang, W.-J., Staels, B., Deprez, B., & Deprez-Poulain, R. Discovery of insulin-degraded enzyme inhibitors by kinetic target-guided synthesis: from structure to cellular activity 52nd International Conference on Medicinal Chemistry, RICT 2016, Interfacing Chemical Biology and Drug Discovery, Caen, Normandy, France, 6th-8th July,2016.
  • Hermant, P., Piveteau, C., Biela, A., Bosc, D., Roignant, M., Deprez, B., & Deprez-Poulain, R. Hit-to-Lead forecasting tools to prevent hydroxamic acids esterasic-metabolism in different species 52nd International Conference on Medicinal Chemistry, RICT 2016, Interfacing Chemical Biology and Drug Discovery, Caen, Normandy, France 6th-8th July,2016.
  • Hermant, P., Piveteau, C., Biela, A., Bosc, D., Roignant, M., Deprez, B., & Deprez-Poulain, R. Plasma and Microsomal Esterases involvement in the Metabolism of Hydroxamic acids in two species. 2"rd Young Research Fellow Meeting of the SCT, Lille, France, 15th-17th Feb.,2016.
  • Jakhlal, J., Hennuyer, N., Charton, J., Dumont, J., Dassonneville, S., Bosc, D., Ronco, C., Florence, L., Tang, W. J., Staels, B., Deprez, B., & Deprez-Poulain, R. Kinetic Target-Guided Synthesis: application for Insulin-Degraded Enzyme inhibitors 23rd Young Research Feloow Meeting of the SCT, Lille, France, 15th-17th Feb.,2016.

2015

  • Hermant, P., Berte, G., Bosc, D., Marechal, X., Gauriot, M., Hennuyer, N., Leroux, F., Charton, J., Lippens, G., Tang, W. J., Staels, B., Deprez, B., & Deprez-Poulain, R. Lead Characterization and physics properties 19 NMR, Formulation and XRay approach 2nd NovAliX Conference - Biophysics in Drug Discovery, Strasbourg, France, 9th-12th Jun,2015.
  • Hermant, P., Jakhlal, J., Deprez-Poulain, R., Hennuyer, N., Ronco, C., Bosc, D., Marechal, M., Gauriot, M., Berte, G., Leroux, F., Charton, J., Tang, W. J., Staels, B., & Deprez, B. From in situ click to vivo: Inhibitors of Insulin Degrading Enzyme 22nd SCT Young Fellow Meeting, Biocitech, Romainville, France, 4-6th February,2015.
  • Deprez-Poulain, R., Hennuyer, N., Ronco, C., Bosc, D., Marechal, X., Gauriot, M., Berte, G., Leroux, F., Charton, J., Tang, W. J., Staels, B., van Endert, P., & Deprez, B. From in situ click to vivo: inhibitors of Insulin Degrading Enzyme EFMC-ISMC 2014, XXIII International Symposium on Medicinal Chemistry, Lisbon, Portugal, 7th-11th September,2014.
  • Bosc, D., Marechal, X., Charton, J., Totobenazara, J., Leroux, F., Piveteau, C., Tang, W. J., Deprez, B., & Deprez-Poulain, R. Discovery via target-guided synthesis and optimization of Insulin-Degrading Enzyme inhibitors. 97th Canadian Chemistry Conference and Exhibition, Vancouver, Canada, 1st-5th Jun,2014.
  • Ronco, C., Berte, G., Bosc, D., Marechal, X., Gauriot, M., Hennuyer, N., Leroux, F., Charton, J., Lippens, G., Tang, W. J., Staels, B., Deprez, B., & Deprez-Poulain, R. X-ray crystallography, kinetic target-guided synthesis to unravel the mode of action of insulin degrading enzyme modulators XXIst Young Research Fellow Meeting of the SCT, Montpellier, France, 24th-25th Mar,2014.
  • Deprez-Poulain, R., Bosc, D., Leroux, F., Charton, J., Tang, W. J., & Deprez, B. Discovery and optimization of Insulin-Degrading Enzyme inhibitors by screening and target-guided synthesis: from structure to cellular activity. 17th RSC/SCI Medicinal Chemistry Symposium, Cambridge, UK, 8th-11th September,2013.
  • Berte, G., Elbakali, J., Wen, X., Deprez, B., & Deprez-Poulain, R. Indole priviledged structures: deciphering the regioselectivity of Larock synthesis Journée des Jeunes Chercheurs SCT, Romainville, France, 7th-8th February,2013.
  • Bosc, D., Marechal, X., Charton, J., Totobenazara, J., Leroux, F., Piveteau, C., Tang, W. J., Deprez, B., & Deprez-Poulain, R. Discovery via in situ click chemistry and structure activity relationships of inhibitors of Insulin-Degrading Enzyme. Journée des Jeunes Chercheurs SCT, Romainville, France, 7th-8th February,2013.
  • Bosc, D., Marechal, X., Charton, J., Verdelet, T., Berte, G., Totobenazara, J., Leroux, F., Piveteau, C., Tang, W. J., Deprez, B., & Deprez-Poulain, R. Discovery via in situ click chemistry and structure activity relationships of inhibitors of Insulin-Degrading Enzyme Rencontres PRIM de la Chimie, de la Biologie et de la Physique, Lille, France, 28th May,2013.
  • Berte, G., Elbakali, J., Wen, X., Deprez, B., & Deprez-Poulain, R. Indole priviledged structures: deciphering the regioselectivity of Larock synthesis Rencontres PRIM de la Chimie, de la Biologie et de la Physique, Lille, France, 28th May,2013.
  • Bosc, D., Marechal, X., Charton, J., Verdelet, T., Berte, G., Totobenazara, J., Leroux, F., Piveteau, C., Tang, W. J., Deprez, B., & Deprez-Poulain, R. Discovery via in situ click chemistry and structure activity relationships of inhibitors of Insulin-Degrading Enzyme International Conference on Medicinal Chemistry, Drug Dicovery and Selection, 49th RICT, Nice, France, 3rd-5th July,2013.
  • Deprez-Poulain, R., Gauriot, M., Charton, J., Leroux, F., Landry, V., Totobenazara, J., Elbakali, J., Wen, X., Guo, Q., Tang, W. J., & Deprez, B. Discovery of Insulin Degrading-Enzyme modulators: challenges for the validation of a cryptidase as a biological target SCI-RSC Medicinal Chemistry, Cambridge, UK, 11th-14th Sep.,2011.
  • Gauriot, M., Leroux, F., Landry, V., Tang, W. J., Guo, Q., Deprez, B., Charton, J., & Deprez-Poulain, R. Pharmacomodulation of a substrate-dependent modulator of Insulin-Degrading Enzyme. 46th RICT International Conference on Medicinal Chemistry, Reims, France, 30th Jun. - 2nd Jul.,2010.
  • Deprez-Poulain, R., Charton, J., Gauriot, M., Landry, V., Leroux, F., Tang, W.-J., & Deprez, B. A New Concept for the control of protease activity: Substrate-Dependent Modulation. EFMC-International Sympsiomon Medicinal Chemistry, Brussels, Belgium, 5-9th Sept.,2010.
  • Totobenazara, J., Leroux, F., Landry, V., Tang, W. J., Deprez, B., Deprez-Poulain, R., & Charton, J. Using in situ click chemistry for the discovery of new Insulin Degrading Enzyme inhibitors International Meeting on Drug Discovery 46th RICT, Reims, France, 30th Jun.-2nd Jul,2010.
  • Deprez-Poulain, R., Leroux, F., Landry, V., Gauriot, M., Totobenazara, J., Guo, Q., Tang, W.-J., Charton, J., & Deprez, B. Discovery of Insulin Degrading Enzyme Modulators 15th RSC-SCI Medicinal Chemistry, Cambridge, UK, 6-9th September,2009.
  • Leroux, F., Landry, V., Host, H., Delaroche, S., Gauriot, M., Déprez, B., Déprez-Poulain, R., & Charton, J. Biological screening for identifying inhibitors of the Insulin Degrading Enzyme. XVIème Journée Jeunes Chercheurs, SCT, Paris, France, February 5th,2009.

Awards

  • Best Poster Prize RICT-2013, to Damien Bosc. Discovery via in situ click chemistry and structure activity relationships of inhibitors of Insulin-Degrading Enzyme, Nice, France.
  • Best Poster Presentation EFMC ISMC 2010. 5-9th Sept: Deprez-Poulain, R .A New Concept for the control of protease activity: Substrate-Dependent Modulation.
  • Prix d'Encouragement à la Recherche 2009 - SCT Servier.  Deprez-Poulain, R.
  • FRM Prize (Fondation pour la Recherche Médicale, Comité Nord-Pas-de-Calais, Oct. 2007) for this project focusing on targets involved in Alzheimer’s disease.

National and International collaborations

  • Pr. Staels & Dr Hennuyer, U1011 INSERM, Lille Pasteur Institute, and University Lille II, Lille. Cell biology of diabetes.
  • Pr Tang , Ben-May Institute  (University of Chicago) -IDE protein engineering, 3D structure and protein-ligand X-Ray experiments.
  • Pr. van Endert, U1013 INSERM, Hopital Necker. Cell biology of diabetes.
  • Dr Sperandio - MTi Inserm, University of Paris Diderot. Molecular modelling of compounds, ligand protein interactions and docking
  • Dr Hamdane,  JPARC, Inserm Lille. Cell biology of Alzheimer.
  • Dr Morelli, Dr Wappner, Instituto Leloir, Buenos Aires, Argentina.

Grants

  • ANR JCC  2012-2013 CHEM-Cryptidases
  • FRM Chimie pour la Medecine 2012-2014 _ DCM20111223046
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