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

Résultats de recherche: Contribution à un événement scientifique (non publié)Poster

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Résumé

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.
langue originaleAnglais
PagesBook of Abstracts, 25èmes Journées Franco-belges de Pharmacochimie, 19-20/05/11, Liège, p. 19
Nombre de pages1
étatPublié - 2011
Evénement 25èmes Journées Franco-belges de Pharmacochimie - Liège, Belgique
Durée: 19 mai 201120 mai 2011

Une conférence

Une conférence 25èmes Journées Franco-belges de Pharmacochimie
PaysBelgique
La villeLiège
période19/05/1120/05/11

Empreinte digitale

Tryptophan Oxygenase
Ralstonia
Posters
Neoplasms
Tryptophan
Databases
Indoleamine-Pyrrole 2,3,-Dioxygenase
Quinolinic Acid
Software Design
Kynurenine
Organized Financing
Enzymes
Immunosuppressive Agents
Immunotherapy
Immunosuppression
Immune System
Vaccination
T-Lymphocytes
Therapeutics

Citer ceci

Moineaux, L., Charlier, C., Dolusic, E., Larrieu, P., Pilotte, L., Colau, D., ... 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 présenté � 25èmes Journées Franco-belges de Pharmacochimie, Liège, Belgique.
Moineaux, Laurence ; Charlier, Caroline ; Dolusic, Eduard ; Larrieu, Pierre ; Pilotte, Luc ; Colau, Didier ; Stroobant, Vincent ; Galleni, Moreno ; Masereel, Bernard ; Van den Eynde, Benoît ; Wouters, Johan ; Frédérick, Raphaël. / Tryptophan 2,3-dioxygenase (TDO) inhibitors : Identification of new scaffolds using virtual screening. Poster présenté � 25èmes Journées Franco-belges de Pharmacochimie, Liège, Belgique.1 p.
@conference{f9256bfd1aa8444faa2df0d8a7c52bfd,
title = "Tryptophan 2,3-dioxygenase (TDO) inhibitors : Identification of new scaffolds using virtual screening",
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 T{\'e}l{\'e}vie (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.",
author = "Laurence Moineaux and Caroline Charlier and Eduard Dolusic and Pierre Larrieu and Luc Pilotte and Didier Colau and Vincent Stroobant and Moreno Galleni and Bernard Masereel and {Van den Eynde}, Beno{\^i}t and Johan Wouters and Rapha{\"e}l Fr{\'e}d{\'e}rick",
year = "2011",
language = "English",
pages = "Book of Abstracts, 25{\`e}mes Journ{\'e}es Franco--belges de Pharmacochimie, 19--20/05/11, Li{\`e}ge, p. 19",
note = "25{\`e}mes Journ{\'e}es Franco-belges de Pharmacochimie ; Conference date: 19-05-2011 Through 20-05-2011",

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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', 25èmes Journées Franco-belges de Pharmacochimie, Liège, Belgique, 19/05/11 - 20/05/11 p. Book of Abstracts, 25èmes Journées Franco-belges de Pharmacochimie, 19-20/05/11, Liège, p. 19.

Tryptophan 2,3-dioxygenase (TDO) inhibitors : Identification of new scaffolds using virtual screening. / Moineaux, Laurence; Charlier, Caroline; Dolusic, Eduard; Larrieu, Pierre; Pilotte, Luc; Colau, Didier; Stroobant, Vincent; Galleni, Moreno; Masereel, Bernard; Van den Eynde, Benoît; Wouters, Johan; Frédérick, Raphaël.

2011. Book of Abstracts, 25èmes Journées Franco-belges de Pharmacochimie, 19-20/05/11, Liège, p. 19 Poster présenté � 25èmes Journées Franco-belges de Pharmacochimie, Liège, Belgique.

Résultats de recherche: Contribution à un événement scientifique (non publié)Poster

TY - CONF

T1 - Tryptophan 2,3-dioxygenase (TDO) inhibitors : Identification of new scaffolds using virtual screening

AU - Moineaux, Laurence

AU - Charlier, Caroline

AU - Dolusic, Eduard

AU - Larrieu, Pierre

AU - Pilotte, Luc

AU - Colau, Didier

AU - Stroobant, Vincent

AU - Galleni, Moreno

AU - Masereel, Bernard

AU - Van den Eynde, Benoît

AU - Wouters, Johan

AU - Frédérick, Raphaël

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

M3 - Poster

SP - Book of Abstracts, 25èmes Journées Franco-belges de Pharmacochimie, 19-20/05/11, Liège, p. 19

ER -

Moineaux L, Charlier C, Dolusic E, Larrieu P, Pilotte L, Colau D et al.. Tryptophan 2,3-dioxygenase (TDO) inhibitors : Identification of new scaffolds using virtual screening. 2011. Poster présenté � 25èmes Journées Franco-belges de Pharmacochimie, Liège, Belgique.