Enzyme and receptor inhibitors group

Group Leader: Pascale Moreau

Research subject

Our research interests mainly focus on the design, synthesis and biological evaluation of heteroaromatic compounds that inhibit kinases involved in cancer, neurodegenerative diseases or pain. In these projects we develop ATP-competitive inhibitors of kinases (CDK, Pim, Dyrk1A…). The design and synthesis of new compounds are carried on in our lab while biological evaluations are performed in collaboration with biologist teams.
 

Research topics

  • Organic synthesis (design, methodology, structural characterization), compounds of biological interest (antitumor, antiparasitic, neurodegenerative diseases, pain).
  • Heteroaromatics: indoles, indazoles, quinoline , aminopyrimidines…
  • Molecular Modelling.
 

Collaborations

  • University of Bergen, Norway: Study of the potency of the prepared compounds toward Acute Myeloid Leukemia.
  • Blokhin Cancer Center, Moscow, Russian Federation: DNA interactions, antiproliferative activities.
  • Station Biologique de Roscoff (France): Study of the potency/selectivity of the prepared compounds to inhibit different kinases.
  • University of Turku, Finland: Study of the Pim-1 kinase function.
  • Oxford University, Angleterre: Crystallographic studies.
  • Laboratoire Neuro-Dol, UMR INSERM 1107, Université Clermont Auvergne: evaluation of analgesic effect on animal models.
 

Contracts

  • Institut National du Cancer, Plan Cancer PCSI (2019-2021): Synthesis and biological evaluation of specific Haspin inhibitors for the development of new anticancer therapies, coordinator Pascale Moreau.
  • Région Auvergne-Rhône-Alpes, Pack Ambition International (2020): Selective cytotoxic agents for the treatment of acute myeloid leukemia, coordinator Fabrice Anizon.
  • Ligue Contre le Cancer – Comité Auvergne (2019): Design, synthesis and biological evaluation of specific haspin inhibitors for the development of novel anti-cancer therapies, coordinator Pascale Moreau.
  • Programme Nouveau Chercheur, région Auvergne (2014-2016): Design and Synthesis of Dyrk1A inhibitors, coordinator F. Giraud.
  • PEPS de site Clermont-Ferrand (2015/2016): Design, synthesis and biological evaluation of PKCγ inhibitors for the study and treatment of mechanical allodynia, coordinator F. Anizon.
 

 

Recent publications

  • A. Visseq, A. Descheemaeker, N. Pinto-Pardo, L. Nauton, V. Théry, F. Giraud, I. Abrunhosa-Thomas, A. Artola, F. Anizon, R. Dallel, P. Moreau. Pyridin-2(1H)one derivatives: a possible new class of therapeutics for mechanical allodynia. European Journal of Medicinal Chemistry, in press, doi: 10.1016/j.ejmech.2019.111917
  • N. M. Brikci-Nigassa, L. Nauton, P. Moreau, O. Mongin, R. E. Duval, L. Picot, V. Thiéry, M. Souab, B. Baratte, S. Ruchaud, S. Bach, R. Le Guevel, G. Bentabed-Ababsa, W. Erb, T. Roisnel, V. Dorcet, F. Mongin Functionalization of 9-thioxanthone at the 1-position: From arylamino derivatives to [1]benzo(thio)pyrano[4,3,2-de]benzothieno[2,3-b]quinolines of biological interest. Bioorganic Chemistry, in press, doi: 10.1016/j.bioorg.2019.103347
  • F. Giraud, E. Pereira, F. Anizon, P. Moreau. Synthesis and applications of dihydropyrrolocarbazoles. European Journal of Organic Chemistry 2019, 5025–5042, doi: 10.1002/ejoc.201900269.
  • R. Bjørnstad, R. Aesoy, Ø. Bruserud, A. K. Brenner, F. Giraud, T. H. Dowling, G. Gausdal, P. Moreau, S. O. Døskeland, F. Anizon, Lars Herfindal. A kinase inhibitor with anti-Pim kinase activity is a potent and selective cytotoxic agent towards acute myeloid leukemia. Molecular Cancer Therapeutics 2019, 18, 567–578, doi: 10.1158/1535-7163.MCT-17-1234.
  • H. Tazarki, W. Zeinyeh, Y. J Esvan, S. Knapp, D. Chatterjee, M. Schröder, A. C. Joerger, J. Khiari, B. Josselin, B. Baratte, S. Bach, S. Ruchaud, F. Anizon, F. Giraud, P. Moreau. New pyrido[3,4-g]quinazoline derivatives as CLK1 and DYRK1A inhibitors: synthesis, biological evaluation and binding mode analysis. European Journal of Medicinal Chemistry 2019, 166, 304–317, doi: 10.1016/j.ejmech.2019.01.052.
  • W. Zeinyeh, Y.  J. Esvan, B. Josselin, B. Baratte, S. Bach, L. Nauton, V. Théry, S. Ruchaud, F. Anizon, F. Giraud, P. Moreau. Kinase inhibitions in pyrido[4,3-h] and [3,4-g]quinazolines: Synthesis, SAR and molecular modeling studies. Bioorganic and Medicinal Chemistry 2019, 27, 2083–2089, doi: 10.1016/j.bmc.2019.04.005.
  • B. Douara, Y.J. Esvan, E. Pereira, F. Giraud, Y.L. Volodina, D.N. Kaluzhny, A.A. Shtil, F. Anizon, P. Moreau. Synthesis and antiproliferative evaluation of glucosylated pyrazole analogues of K252c. Tetrahedron 2018, 74, 892-901, doi: 10.1016/j.tet.2018.01.017.
  • W. Zeinyeh, Y.J. Esvan, L. Nauton, N. Loaëc, L. Meijer, V. Théry, F. Anizon, F. Giraud, P. Moreau. Synthesis and preliminary in vitro kinase inhibition evaluation of new diversely substituted pyrido[3,4-g]quinazoline derivatives. Bioorganic & Medicinal Chemistry Letters 2016, 26, 4327-4329, doi: 10.1016/j.bmcl.2016.07.032
  • Y.J. Esvan, F. Giraud, E. Pereira, V. Suchaud, L. Nauton, V. Théry, L.G. Dezhenkova, D.N. Kaluzhny, V.N. Mazov, A.A. Shtil, F. Anizon, P. Moreau. Synthesis and biological activity of pyrazole analogues of the staurosporine aglycon K252c. Bioorganic & Medicinal Chemistry 2016, 24, 3116-3124, doi: 10.1016/j.bmc.2016.05.032.
  • P. Moreau, F. Anizon, F. Giraud, Y.J. Esvan. Heteroaromatic Pim kinase inhibitors containing a pyrazole moiety. Recent Patents on Anti-Cancer Drug Discovery 2016, 11, 309-321, doi: 10.2174/1574892811666160519141628.Y.J. Esvan, W. Zeinyeh, T. Boibessot, L. Nauton, V. Théry, S. Knapp, A. Chaikuad, N. Loaëc, L. Meijer, F. Anizon, F. Giraud, P. Moreau. Discovery of pyrido[3,4-g]quinazoline derivatives as CMGC family protein kinase inhibitors : design, synthesis, inhibitory potency and X-ray co-crystal structure. European Journal of Medicinal Chemistry 2016, 118, 170-177, doi: 10.1016/j.ejmech.2016.04.004.
  • F. Giraud, M. Bourhis, E. Ebrahimi, L. Herfindal, R.R. Choudhury, R. Bjørnstad, S.O. Døskeland, F. Anizon, P. Moreau. Synthesis and activities of new indolopyrrolobenzodiazepine derivatives toward Acute Myeloid Leukemia cells. Bioorganic and Medicinal Chemistry 2015, 23, 7313-7323, doi: 10.1016/j.bmc.2015.10.031.
  • N.M. Santio, S.K. Eerola, I. Paatero, J. Yli-Kauhaluoma, F. Anizon, P. Moreau, J. Tuomela, P. Härkönen, P.J. Koskinen. Pim kinases promote migration and metastatic growth of prostate cancer xenografts. PLoS One 2015, 10, e0130340, doi: 10.1371/journal.pone.0130340.
  • F. Giraud, F. Anizon, P. Moreau. Advances in the synthesis and kinase inhibitory potencies of non-fused indazole derivatives. Targets in Heterocyclic Systems : Chemistry and Properties. O.A. Attanasi, R. Noto, D. Spinelli, Eds. Italian Society of Chemistry, 2014, 18, 1-28, https://www.soc.chim.it/sites/default/files/ths/18/chapter_1.pdf
  • V. Suchaud, L. Gavara, F. Giraud, L. Nauton, V. Théry, F. Anizon, P. Moreau. Synthesis of pyrazolo[4,3-a]phenanthridines, a new scaffold for Pim kinase inhibition. Bioorganic and Medicinal Chemistry 2014, 22, 4704–4710, doi: 10.1016/j.bmc.2014.07.011.
  • F. Giraud, M. Bourhis, L. Nauton, V. Théry, L. Herfindal, S.O. Døskeland, F. Anizon, P. Moreau. New N-1,N-10-bridged pyrrolo[2,3-a]carbazole-3-carbaldehydes : synthesis and biological activities. Bioorganic Chemistry 2014, 57, 108–115, doi: 10.1016/j.bioorg.2014.09.004.
  • P. Moreau, L.G. Dezhenkova, F. Anizon, L. Nauton, V. Théry, S. Liang, D.N. Kaluzhny, A.A. Shtil. New Inhibitor of Pim-1/3 Protein Kinases Sensitizes Human Colon Carcinoma Cells to Doxorubicin. Anti-Cancer Agents in Medicinal Chemistry 2014, 14, 1228–1236, doi: 10.2174/1871520614666140825124456.
  • E. Pereira, A. Youssef, M. El-Ghozzi, D. Avignant, J. Bain, M. Prudhomme, F. Anizon, P. Moreau. Synthesis of dipyrrolo[3,4-a:3,4-c]carbazoles : new kinase inhibitors. Tetrahedron Letters 2014, 55, 834–837, doi: 10.1016/j.tetlet.2013.12.027.
  • V. Suchaud, L. Gavara, E. Saugues, L. Nauton, V. Théry, F. Anizon, P. Moreau. Identification of 1,6-dihydropyrazolo[4,3-c]carbazoles and 3,6-dihydropyrazolo[3,4-c]carbazoles as new Pim kinase inhibitors. Bioorg. Med. Chem. 2013, 21, 4102-4111, doi: 10.1016/j.bmc.2013.05.011.
  • L. Gavara, V. Suchaud, L. Nauton, V. Théry, F. Anizon, P. Moreau. Identification of pyrrolo[2,3-g]indazoles as new Pim kinase inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 2298-2301, doi: 10.1016/j.bmcl.2013.02.074.
  • G. Sarek, L. Ma, J. Enbäck, A. Järviluoma, P. Moreau, J. Haas, A. Gessain, P.J. Koskinen, P. Laakkonen, P.M. Ojala. Kaposi’s sarcoma herpes virus lytic replication compromises apoptotic response to p53 reactivation in virus-induced lymphomas. Oncogene 2013, 32, 1091-1098, doi: 10.1038/onc.2012.118.