Metalloproteases and modulators

Team

  • Team Leader: Pr Rebecca Deprez-Poulain PhD PharmD MRSC
  • Damien Bosc PhD, Ass. Prof
  • Ronan Gealageas PhD, Postdoc
  • Kelly CHeng Phd, PostDoc
  • Paul Hermant PhD student
  • Bao Vy Lam PhD, Postdoc
  • Jouda Jahklal PhD former Postdoc
  • Lucie Maingot PhD former Postdoc

Mission

Target metalloproteases thanks to a chemo-genomic strategy.

Approach

Modern chemistry techniques allow for the generation of a vast number of compounds and an even greater amount of data. Chemoinformatics refers to the building of electronic databases of the chemical and biological properties of large numbers of chemical compounds. One application of the mining of very large datasets of chemical and biological information is chemical genomics or "chemogenomics", which uses drug-like compounds as molecular probes for cell-biology research, to clarify for example the function of a certain gene product. Because it integrates chemistry and biology already in an early stage in the research process, "chemogenomics" is a technologic bridge between genetic and therapeutic research areas. Continuation of a pilot chemogenomics project supported by the Nord-Pas-de Calais Region and FEDER, this project federates several labs around the study of metalloproteases, according to a strategy which takes root into the regional scientific environment, with special focus on the exploitation of the Regional Screening plateform maintained in our lab and of a DNA microarray designed to represent all expressed human metalloproteases

Metalloproteases are a class of proteins involved in diverse and important biological phenomena such as cell proliferation, signalisation, multiplication and migration, hormonal signalisation, angiogenesis, pathogen growth. Numerous inhibitors of this enzyme class are described and some are important therapeutic classes: ACE or NEP inhibitors. This context justifies for the systematic search of metalloproteases implication in orphan pathologies, as well as for their expression, purification and crystallisation, or for the design and synthesis of a targeted library of inhibitors.

Latest results

For results on hIDE and hERAPs consult the relative webpages.

Having a strong background in the inhibition of parasitic metalloproteases (PfA-M1) (http://dx.doi.org/10.1021/jm061169b) and their human orthologues (APN) (http://dx.doi.org/10.1016/j.bmc.2006.10.010), our group has designed and synthesized 1500 Zinc ligands that will be tested on a panel of 10 metalloproteases. The goals of the project are 1/ finding inhibitors of the chosen targets, 2/ validating these targets in vitro and in vivo in cellular or animal models, 3/ developing new drug lead series. Already 5 screening campains on metalloproteases have been performed see the poster proposed at the SBS (Society for Biomecular Screening) 15th Annual Meeting Apr. 26-30 2009. Using this strategy, novel drug-like inhibitors of Neutral Endopeptidase and Aggrecanase-2 have been found and optimized. Also the first modulators of insulin degrading enzyme have been found.

Deprez-Poulain, R., Flipo, M., Piveteau, C., Leroux, F., Dassonneville, S., Florent, I., Maes, L., Cos, P., & Deprez, B. Structure-Activity Relationships and Blood Distribution of Antiplasmodial Aminopeptidase-1 Inhibitors. Journal of Medicinal Chemistry,2012, 55(24): 10909. doi: 10.1021/jm301506h

Chemical strategy

When targeting metalloproteases, a ZBG is necessary to bind to the Zinc ion and sets the rest of the molecule in the active site. Using hydroxamate is convenient to achieve good activity at the screening stage because this function is one of the best Zn ligand. Nevertheless, a high binding to the target can be achieved with a "softer" ZBG, provided that the rest of the molecule fits nicely in the binding pocket. Furthermore, because hydroxamic acids are often poorly absorbed and are prone to metabolic degradation and glucuronidation, there has been considerable interest in discovering alternative groups that can be incorporated in the structures of metalloproteases inhibitors. The search of relevant new zing binding groups is widely investigated. ZBG can be classified in two classes 1) monodentate that include thiols, carboxylic acids, acidic heterocycles, phosphinic acids...2) bidentate that include hydroxamate and hydroxypyridones. Recent examples of the use of heterocyclic ZBGs include hydantoines, triazolones and imidazolones as inhibitors of TACE (TNF-alpha converting enzyme) or tetrazoles as inhibitors of metallo-beta-lactamase.

We have developped chemical strategies to synthesize in parallel, either using solution-phase or solid-phase synthesis, the following compounds: tetrazoles, squaric acid derivatives, 1,3,4-triazole-thiols -1,2,4-oxadiazol-ones or –thiones…

National and international collaborations

  • Pr Tang , Ben-May Institute  (University of Chicago) -IDE protein engineering, 3D structure and protein-ligand X-Ray experiments.
  • Dr Sperandio - MTi Inserm, University of Paris Diderot. Molecular modelling of compounds, ligand protein interactions and docking.
  • Pr. Nagase Imperial College, London, UK.
  • Pr Stratikos Demokritos Center, Athens, Belgium.
  • Pr Lijnen University of Ghent, Belgium.

Publications

  • Boiteau, J.-G., Ouvry, G., Arlabosse, J.-M., Astri, S., Beillard, A., Bhurruth-Alcor, Y., Bonnary, L., Bouix-Peter, C., Bouquet, K., Bourotte, M., Cardinaud, I., Comino, C., Deprez, B., Duvert, D., Féret, A., Hacini-Rachinel, F., Harris, C. S., Luzy, A.-P., Mathieu, A., Millois, C., Orsini, N., Pascau, J., Pinto, A., Piwnica, D., Polge, G., Reitz, A., Reversé, K., Rodeville, N., Rossio, P., Spiesse, D., Tabet, S., Taquet, N., Tomas, L., Vial, E., & Hennequin, L. F. Discovery and process development of a novel TACE inhibitor for the topical treatment of psoriasis. Bioorganic & Medicinal Chemistry,2017: in press. 10.1016/j.bmc.2017.07.054
  • Hermant, P., Bosc, D., Piveteau, C., Gealageas, R., Lam, B. V., Ronco, C., Roignant, M., Tolajanahary, H., Jean, L., Renard, P.-Y., Lemdani, M., Bourotte, M., Herledan, A., Bedart, C., Biela, A., Leroux, F., Deprez, B., & Deprez-Poulain, R. Controlling Plasma Stability of Hydroxamic Acids: A MedChem Toolbox. Journal of Medicinal Chemistry,2017. in press 10.1021/acs.jmedchem.7b01444
  • Mpakali, A., Giastas, P., Deprez-Poulain, R., Papakyriakou, A., Koumantou, D., Gealageas, R., Tsoukalidou, S., Vourloumis, D., Mavridis, I. M., Stratikos, E., & Saridakis, E. Crystal Structures of ERAP2 Complexed with Inhibitors Reveal Pharmacophore Requirements for Optimizing Inhibitor Potency. ACS Medicinal Chemistry Letters,2017, 8(3): 333-337.doi:10.1021/acsmedchemlett.6b00505
  • Ouvry, G., Berton, Y., Bhurruth-Alcor, Y., Bonnary, L., Bouix-Peter, C., Bouquet, K., Bourotte, M., Chambon, S., Comino, C., Deprez, B., Duvert, D., Duvert, G., Hacini-Rachinel, F., Harris, C. S., Luzy, A.-P., Mathieu, A., Millois, C., Pascau, J., Pinto, A., Polge, G., Reitz, A., Reversé, K., Rosignoli, C., Taquet, N., & Hennequin, L. F. Identification of novel TACE inhibitors compatible with topical application. 2017 Bioorganic & Medicinal Chemistry Letters,in press.doi:10.1016/j.bmcl.2017.02.035
  • Bauters, D., Scroyen, I., Deprez-Poulain, R., & Lijnen, H. R. ADAMTS5 promotes murine adipogenesis and visceral adipose tissue expansion. Thromb Haemost,2016, 116(4). doi:10.1160/th16-01-0015
  • Letronne, F., Laumet, G., Ayral, A. M., Chapuis, J., Demiautte, F., Laga, M., Vandenberghe, M. E., Malmanche, N., Leroux, F., Eysert, F., Sottejeau, Y., Chami, L., Flaig, A., Bauer, C., Dourlen, P., Lesaffre, M., Delay, C., Huot, L., Dumont, J., Werkmeister, E., Lafont, F., Mendes, T., Hansmannel, F., Dermaut, B., Deprez, B., Herard, A. S., Dhenain, M., Souedet, N., Pasquier, F., Tulasne, D., Berr, C., Hauw, J. J., Lemoine, Y., Amouyel, P., Mann, D., Deprez-Poulain, R., Checler, F., Hot, D., Delzescaux, T., Gevaert, K., & Lambert, J. C. ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimer's Disease. EBioMedicine,2016: in press. doi:10.1016/j.ebiom.2016.06.002 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
  • Elbakali, J., Gras, H., Maingot, L., Deprez, B., Dumont, J., Leroux, F., & Deprez-Poulain, R. Inhibition of aggrecanase as a therapeutic strategy in osteoarthritis. Future Medicinal Chemistry,2014, 6(12): 1399-1412. 10.4155/FMC.14.84
  • Maingot, L., Elbakali, J., Dumont, J., Bosc, D., Cousaert, N., Urban, A., Deglane, G., Villoutreix, B., Nagase, H., Sperandio, O., Leroux, F., Deprez, B., & Deprez-Poulain, R. Aggrecanase-2 Inhibitors Based on the Acylthiosemicarbazide Zinc-Binding Group. Eur J Med Chem,2013, 69: 244-261.doi: 10.1016/j.ejmech.2013.08.027
  • Elbakali, J., Maingot, L., Dumont, J., Host, H., Hocine, A., Cousaert, N., Dassonneville, S., Leroux, F., Deprez, B., & Deprez-Poulain, R. Novel Selective Inhibitors of Neutral Endopeptidase: Discovery by Screening and Hit-to-Lead Optimisation. Med.Chem.Comm.,2012, 3: 469-474.. doi:10.1039/C2MD00287F
  • Maingot, L., Leroux, F., Landry, V., Dumont, J., Nagase, H., Villoutreix, B., Sperandio, O., Deprez-Poulain, R., & Deprez, B. New non-hydroxamic ADAMTS-5 inhibitors based on the 1,2,4-triazole-3-thiol scaffold. Bioorganic & Medicinal Chemistry Letters,2010, 21: 6213-6216.
  • Flipo, M., Charton, J., Hocine, A., Dassonneville, S., Deprez, B., & Deprez-Poulain, R. Hydroxamates: Relationships between structure and plasma-stability. J Med Chem,2009, 52(21): 6790-6802.
  • Charton, J., Deprez-Poulain, R., Hennuyer, N., Tailleux, A., Staels, B., & Deprez, B. Novel non-carboxylic acid retinoids: 1,2,4-Oxadiazol-5-one derivatives. Bioorganic & Medicinal Chemistry Letters,2009, 19(2): 489-492.
  • Vaccher, M.-P.; Charton, J.; Guelzim, A.; Caignard, D.-H.; Bonte, J.-P.; Vaccher, C., Preparative Enantiomeric Separation of Potent AMP-Activated Protein Kinase Activator by HPLC on Amylose-Based Chiral Stationary Phase. Determination of Enantiomeric Purity and Assignment of Absolute Configuration. J. Pharm. Biomed. Anal. 2008,5, 920-928.
  • Charton, J.; Charruault, L.; Deprez, B.; Deprez-Poulain, R., Alkylsquarates as key intermediates for the rapid preparation of original drug-inspired compounds. Combinatorial Chemistry and High Throughput Screening 2008, 11, (4) 294-303.
  • Cousaert, N.; Willand, N.; Gesquiere, J.-C.; Tartar, A.; Deprez, B.; Deprez-Poulain, R.,
    Original loading and Suzuki conditions for the solid-phase synthesis of biphenyltetrazoles. Application to the first solid-phase synthesis of irbesartan. Tetrahedron Letters 2008, 49, (17), 2743.
  • Charton, J.; Cousaert, N.; Bochu, C.; Willand, N.; Deprez, B.; Deprez-Poulain, R., A versatile solid-phase synthesis of 3-aryl-1,2,4-oxadiazolones and analogues. Tetrahedron Lett. 2007, 48, (8), 1479-1483.
  • Deprez-Poulain, R. F.; Charton, J.; Leroux, V.; Deprez, B. P., Convenient synthesis of 4H-1,2,4-triazole-3-thiols using di-2-pyridylthionocarbonate. Tetrahedron Lett. 2007, 48, (46), 8157.
  • Flipo, M.; Beghyn, T.; Charton, J.; Leroux, V. A.; Deprez, B. P.; Deprez-Poulain, R. F., A library of novel hydroxamic acids targeting the metallo-protease family: design, parallel synthesis and screening. Bioorg. Med. Chem. 2007, 15, (1), 63-76.
  • Flipo, M.; Beghyn, T.; Leroux, V.; Florent, I.; Deprez, B. P.; Deprez-Poulain, R. F., Novel Selective Inhibitors of the Zinc Plasmodial Aminopeptidase PfA-M1 as Potential Antimalarial Agents. J Med Chem 2007, 50, (6), 1322-1334.
    Deprez-Poulain, R.; Deprez, B., Trends in Hit-to-Lead: An Update. Frontiers in Medicinal Chemistry 2006, 3, (1), 653-673.
  • Deprez-Poulain, R.; Melnyk, P., 1,4-bis(3-aminopropyl)piperazine libraries: from the discovery of classical chloroquine-like antimalarials to the identification of new targets. Comb. Chem. High Throughput Screen. 2005, 8, (1), 39-48.
  • Deprez-Poulain, R.; Deprez, B., Facts, figures and trends in lead generation. Curr. Top. Med. Chem. 2004, 4, (6), 569-80.
  • Flipo, M.; Florent, I.; Grellier, P.; Sergheraert, C.; Deprez-Poulain, R., Design, synthesis and antimalarial activity of novel, quinoline-Based, zinc metallo-aminopeptidase inhibitors. Bioorg. Med. Chem. Lett. 2003, 13, (16), 2659.
  • Ryckebusch, A.; Deprez-Poulain, R.; Maes, L.; Debreu-Fontaine, M. A.; Mouray, E.; Grellier, P.; Sergheraert, C., Synthesis and in vitro and in vivo antimalarial activity of N1-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine derivatives. J Med Chem 2003, 46, (4), 542-57.

Conferences

  • Maingot, L. Discovery of Novel Aggrecanase-2 inhibitors by HTS and hit-to-lead optimisation.,Scientific Day PRIM,Lille,10th Mar 2010.
  • Hermant, P., Piveteau, C., Bosc, D., Biela, A., Roignant, M., Deprez, B., & Deprez-Poulain, R. High-throughput profiling of esterases involved in hydroxamic acids hydrolysis,24th Young Research Fellow Meeting of the SCT,Châtenay Malabry, France,8th-10th February 2017

Poster communications

  • Maingot, L., Host, H., Leroux, F., Cousaert, N., Deprez-Poulain, R., & Deprez, B. Discovery of Neutral Endopeptidase (NEP) Inhibitors by HTS and Hit-to-Lead optimisation. 46th RICT International Conference on Medicinal Chemistry, Reims, France, 30th Jun- 2nd Jul,2010.
  • Maingot, L., Leroux, F., Delaroche, S., Landry, V., Charton, J., Deprez-Poulain, R., & Deprez, B. Discovery of Novel Aggrecanase -2 Inhibitors by screening and optimisation. 3rd International Symposium on Advances in Synthetic and Medicinal Chemistry, Kiev, Ukraine, August 23 - 27,2009.
  • Leroux, F., Host, H., Landry, V., Delaroche, S., Maingot, L., Charton, J., Deprez, B., & Déprez-Poulain, R. An efficient platform to study metalloproteases (P4006) 15th SBS Annual Conference, Lille, France, 26-30 Apr.,2009.
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