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

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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 Galeni (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. A series of vinyl-1H-indoles has been synthesized and their inhibitory potential has been evaluated on TDO of Ralstonia metallidurans (rmTDO) overexpressed in E.coli and purified by affinity chromatography. Crystallographic structure of some analogues was obtained and used as starting point for a docking study of these inhibitors in a model of humanized rmTDO. These data allowbetter understanding of how this family of inhibitors interact with TDO. This process is presented on this poster.
Original languageEnglish
PagesAbstracts, Journée scientifique de la Société royale de chimie (SRC), Gembloux, Belgium, 14 October 2010
Publication statusPublished - 2010
EventJournée scientifique de la Société royale de chimie (SRC) - Gembloux, Belgium
Duration: 14 Oct 2010 → …

Symposium

SymposiumJournée scientifique de la Société royale de chimie (SRC)
CountryBelgium
CityGembloux
Period14/10/10 → …

Fingerprint

Tryptophan Oxygenase
Neoplasms
Tryptophan
Ralstonia
Indoleamine-Pyrrole 2,3,-Dioxygenase
Quinolinic Acid
Kynurenine
Indoles
Posters
Organized Financing
Enzymes
Immunosuppressive Agents
Affinity Chromatography
Immunotherapy
Immunosuppression
Immune System
Vaccination
Escherichia coli
T-Lymphocytes
Therapeutics

Cite this

Moineaux, L., Charlier, C., Dolusic, E., Larrieu, P., Pilotte, L., Colau, D., ... Frédérick, R. (2010). Tryptophan 2,3-dioxygenase (TDO) inhibitors : Identification of new scaffolds using virtual screening. Abstracts, Journée scientifique de la Société royale de chimie (SRC), Gembloux, Belgium, 14 October 2010. Poster session presented at Journée scientifique de la Société royale de chimie (SRC), Gembloux, Belgium.
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 session presented at Journée scientifique de la Société royale de chimie (SRC), Gembloux, Belgium.
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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 Galeni (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. A series of vinyl-1H-indoles has been synthesized and their inhibitory potential has been evaluated on TDO of Ralstonia metallidurans (rmTDO) overexpressed in E.coli and purified by affinity chromatography. Crystallographic structure of some analogues was obtained and used as starting point for a docking study of these inhibitors in a model of humanized rmTDO. These data allowbetter 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 = "2010",
language = "English",
pages = "Abstracts, Journ{\'e}e scientifique de la Soci{\'e}t{\'e} royale de chimie (SRC), Gembloux, Belgium, 14 October 2010",
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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 2010, 'Tryptophan 2,3-dioxygenase (TDO) inhibitors : Identification of new scaffolds using virtual screening', Journée scientifique de la Société royale de chimie (SRC), Gembloux, Belgium, 14/10/10 pp. Abstracts, Journée scientifique de la Société royale de chimie (SRC), Gembloux, Belgium, 14 October 2010.

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.

2010. Abstracts, Journée scientifique de la Société royale de chimie (SRC), Gembloux, Belgium, 14 October 2010 Poster session presented at Journée scientifique de la Société royale de chimie (SRC), Gembloux, Belgium.

Research output: Contribution to conferencePoster

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 - 2010

Y1 - 2010

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 Galeni (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. A series of vinyl-1H-indoles has been synthesized and their inhibitory potential has been evaluated on TDO of Ralstonia metallidurans (rmTDO) overexpressed in E.coli and purified by affinity chromatography. Crystallographic structure of some analogues was obtained and used as starting point for a docking study of these inhibitors in a model of humanized rmTDO. These data allowbetter 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 Galeni (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. A series of vinyl-1H-indoles has been synthesized and their inhibitory potential has been evaluated on TDO of Ralstonia metallidurans (rmTDO) overexpressed in E.coli and purified by affinity chromatography. Crystallographic structure of some analogues was obtained and used as starting point for a docking study of these inhibitors in a model of humanized rmTDO. These data allowbetter understanding of how this family of inhibitors interact with TDO. This process is presented on this poster.

M3 - Poster

SP - Abstracts, Journée scientifique de la Société royale de chimie (SRC), Gembloux, Belgium, 14 October 2010

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. 2010. Poster session presented at Journée scientifique de la Société royale de chimie (SRC), Gembloux, Belgium.