Tryptophan 2,3-dioxygenase (TDO) inhibitors : Identification of new scaffolds using virtual screening

Laurence Moineaux, Caroline Charlier, Eduard Dolusic, Pierre Larrieu, Luc Pilotte, Didier Colau, Vincent Stroobant, Moreno Galleni, Bernard Masereel, Benoît Van den Eynde, Johan Wouters, Raphaël Frédérick

Research output: Contribution to conferencePoster

75 Downloads (Pure)

Abstract

Immunotherapy is a promising novel strategy for cancer therapy. It consists of the therapeutic vaccination of cancer patients to stimulate their (natural) immune system against cancer cells. This approach, however, showed limited efficacy in vivo. Cancer cells are actually able to develop enzymatic mechanisms allowing tumours to resist or escape the immune rejection. Among the enzymes involved, the indoleamine 2,3-dioxygenases IDO and TDO represents potential actors.[1-3] These enzymes catalyse the rapid degradation of tryptophan (Trp) through the kynurenine (KYN) pathway to form quinolinic acid (QA). This results in a local Trp depletion that severely affects the proliferation of T lymphocytes and is thereby profoundly immunosuppressive. This project was funded in part by Télévie (FNRS grant 7.4.543.07) and led in collaboration with the team of Pr Benoit Van Den Eynde (LICR, UCL) and Pr Moreno Galleni (CIP, ULG) aims at developing novel TDO inhibitors using a rational approach. These inhibitors will allow a better understanding of the role of TDO in the phenomenon of immunosuppression, especially in cancerous tumors. In the present poster, we used virtual screening (VS) of the ZINC database of 2.5 million compounds to seek new TDO inhibitory scaffolds. The VS flowchart implemented various filters, including a 3D-database screen, and extensive docking studies in humanized Ralstonia metallidurans TDO (rmTDO), to derive 49 derivatives that were experimentally assayed against the rmTDO. Three compounds showed inhibitory percentage above 50%. These data allow better understanding of how this family of inhibitors interact with TDO. This process is presented on this poster.
Original languageEnglish
PagesBook of Abstracts, 25èmes Journées Franco-belges de Pharmacochimie, 19-20/05/11, Liège, p. 19
Number of pages1
Publication statusPublished - 2011
Event 25èmes Journées Franco-belges de Pharmacochimie - Liège, Belgium
Duration: 19 May 201120 May 2011

Conference

Conference 25èmes Journées Franco-belges de Pharmacochimie
CountryBelgium
CityLiège
Period19/05/1120/05/11

Fingerprint Dive into the research topics of 'Tryptophan 2,3-dioxygenase (TDO) inhibitors : Identification of new scaffolds using virtual screening'. Together they form a unique fingerprint.

  • Projects

    Activities

    • 4 Participation in conference

    Heterocycles in Bio-organic Chemistry

    Eduard Dolusic (Poster)

    27 May 2013

    Activity: Participating in or organising an event typesParticipation in conference

    BOSS XIII - 13th Belgian Organic Synthesis Symposium Louvain, 15 - 20 juillet 2012

    Eduard Dolusic (Poster)

    15 Jul 2012

    Activity: Participating in or organising an event typesParticipation in conference

    JFB 2011.

    Eduard Dolusic (Speaker)

    19 May 201120 May 2011

    Activity: Participating in or organising an event typesParticipation in conference

    Cite this

    Moineaux, L., Charlier, C., Dolusic, E., Larrieu, P., Pilotte, L., Colau, D., Stroobant, V., Galleni, M., Masereel, B., Van den Eynde, B., Wouters, J., & Frédérick, R. (2011). Tryptophan 2,3-dioxygenase (TDO) inhibitors : Identification of new scaffolds using virtual screening. Book of Abstracts, 25èmes Journées Franco-belges de Pharmacochimie, 19-20/05/11, Liège, p. 19. Poster session presented at 25èmes Journées Franco-belges de Pharmacochimie, Liège, Belgium.