coauthor on lecture: Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase (TDO): discovery of an orally active TDO inhibitor.

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

Research output: Contribution in Book/Catalog/Report/Conference proceedingConference contribution

Abstract

Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase (TDO): design, synthesis and preclinical evaluation of novel TDO inhibitors Eduard Dolusic1, Pierre Larrieu,2 Laurence Moineaux,1 Vincent Stroobant,2 Luc Pilotte,2 Didier Colau,2 Benoît Van den Eynde,2 Bernard Masereel,1 Johan Wouters,1 and Raphaël Frédérick1 1. Namur Drug Design and Discovery Center (ND3C), University of Namur, FUNDP, 61 Rue de Bruxelles, 5000 Namur, Belgium 2. Ludwig Institute for Cancer Research (LICR), Université Catholique de Louvain, 74 Avenue Hippocrate, 1200 Brussels, Belgium Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO1) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance, and IDO1 inhibition is an active area of drug development. Recently, the team of Benoit Van den Eynde (LICR, UCL, Belgium) has shown that tryptophan 2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is also expressed in many tumors and that this expression prevents tumor rejection by locally depleting tryptophan. In this communication, a detailed structure-activity study of a series of 3-(2-(pyridyl)ethenyl)indoles targeting TDO will be presented. This study led to the identification of a very potent, selective and orally available TDO inhibitor (LM10) which, upon systemic treatment, restored the ability of mice to reject TDO-expressing tumors. Our results thus describe a new mechanism of tumoral immune resistance based on TDO expression and establish proof-of-concept for the use of TDO inhibitors in cancer therapy.
Original languageEnglish
Title of host publicationBook of Abstracts, Emerging Targets and Treatments: Opportunities and Challenges for Drug Design, Ghent, 25 November 2011
Subtitle of host publicationAnnual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (MedChem 2011)
PagesOC01
VolumeOC01
Publication statusPublished - 2011
EventAnnual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (Medchem 2011) - Gand, Belgium
Duration: 25 Nov 2011 → …

Conference

ConferenceAnnual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (Medchem 2011)
CountryBelgium
CityGand
Period25/11/11 → …

Fingerprint

Tryptophan Oxygenase
Belgium
Tryptophan
Neoplasms
Ruta
Indoleamine-Pyrrole 2,3,-Dioxygenase
Peripheral Tolerance
Indoles
Immune Tolerance
Drug Design
Drug Discovery

Cite this

Dolusic, E., Larrieu, P., Moineaux, L., Stroobant, V., Pilotte, L., Colau, D., ... Frédérick, R. (2011). coauthor on lecture: Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase (TDO): discovery of an orally active TDO inhibitor. In Book of Abstracts, Emerging Targets and Treatments: Opportunities and Challenges for Drug Design, Ghent, 25 November 2011: Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (MedChem 2011) (Vol. OC01, pp. OC01)
Dolusic, Eduard ; Larrieu, Pierre ; Moineaux, Laurence ; Stroobant, Vincent ; Pilotte, Luc ; Colau, Didier ; Van den Eynde, Benoît ; Masereel, Bernard ; Wouters, Johan ; Frédérick, Raphaël. / coauthor on lecture: Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase (TDO): discovery of an orally active TDO inhibitor. Book of Abstracts, Emerging Targets and Treatments: Opportunities and Challenges for Drug Design, Ghent, 25 November 2011: Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (MedChem 2011). Vol. OC01 2011. pp. OC01
@inproceedings{0933047024104ec7bbd58df81d124a91,
title = "coauthor on lecture: Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase (TDO): discovery of an orally active TDO inhibitor.",
abstract = "Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase (TDO): design, synthesis and preclinical evaluation of novel TDO inhibitors Eduard Dolusic1, Pierre Larrieu,2 Laurence Moineaux,1 Vincent Stroobant,2 Luc Pilotte,2 Didier Colau,2 Beno{\^i}t Van den Eynde,2 Bernard Masereel,1 Johan Wouters,1 and Rapha{\"e}l Fr{\'e}d{\'e}rick1 1. Namur Drug Design and Discovery Center (ND3C), University of Namur, FUNDP, 61 Rue de Bruxelles, 5000 Namur, Belgium 2. Ludwig Institute for Cancer Research (LICR), Universit{\'e} Catholique de Louvain, 74 Avenue Hippocrate, 1200 Brussels, Belgium Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO1) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance, and IDO1 inhibition is an active area of drug development. Recently, the team of Benoit Van den Eynde (LICR, UCL, Belgium) has shown that tryptophan 2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is also expressed in many tumors and that this expression prevents tumor rejection by locally depleting tryptophan. In this communication, a detailed structure-activity study of a series of 3-(2-(pyridyl)ethenyl)indoles targeting TDO will be presented. This study led to the identification of a very potent, selective and orally available TDO inhibitor (LM10) which, upon systemic treatment, restored the ability of mice to reject TDO-expressing tumors. Our results thus describe a new mechanism of tumoral immune resistance based on TDO expression and establish proof-of-concept for the use of TDO inhibitors in cancer therapy.",
author = "Eduard Dolusic and Pierre Larrieu and Laurence Moineaux and Vincent Stroobant and Luc Pilotte and Didier Colau and {Van den Eynde}, Beno{\^i}t and Bernard Masereel and Johan Wouters and Rapha{\"e}l Fr{\'e}d{\'e}rick",
year = "2011",
language = "English",
volume = "OC01",
pages = "OC01",
booktitle = "Book of Abstracts, Emerging Targets and Treatments: Opportunities and Challenges for Drug Design, Ghent, 25 November 2011",

}

Dolusic, E, Larrieu, P, Moineaux, L, Stroobant, V, Pilotte, L, Colau, D, Van den Eynde, B, Masereel, B, Wouters, J & Frédérick, R 2011, coauthor on lecture: Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase (TDO): discovery of an orally active TDO inhibitor. in Book of Abstracts, Emerging Targets and Treatments: Opportunities and Challenges for Drug Design, Ghent, 25 November 2011: Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (MedChem 2011). vol. OC01, pp. OC01, Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (Medchem 2011), Gand, Belgium, 25/11/11.

coauthor on lecture: Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase (TDO): discovery of an orally active TDO inhibitor. / Dolusic, Eduard; Larrieu, Pierre; Moineaux, Laurence; Stroobant, Vincent; Pilotte, Luc; Colau, Didier; Van den Eynde, Benoît; Masereel, Bernard; Wouters, Johan; Frédérick, Raphaël.

Book of Abstracts, Emerging Targets and Treatments: Opportunities and Challenges for Drug Design, Ghent, 25 November 2011: Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (MedChem 2011). Vol. OC01 2011. p. OC01.

Research output: Contribution in Book/Catalog/Report/Conference proceedingConference contribution

TY - GEN

T1 - coauthor on lecture: Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase (TDO): discovery of an orally active TDO inhibitor.

AU - Dolusic, Eduard

AU - Larrieu, Pierre

AU - Moineaux, Laurence

AU - Stroobant, Vincent

AU - Pilotte, Luc

AU - Colau, Didier

AU - Van den Eynde, Benoît

AU - Masereel, Bernard

AU - Wouters, Johan

AU - Frédérick, Raphaël

PY - 2011

Y1 - 2011

N2 - Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase (TDO): design, synthesis and preclinical evaluation of novel TDO inhibitors Eduard Dolusic1, Pierre Larrieu,2 Laurence Moineaux,1 Vincent Stroobant,2 Luc Pilotte,2 Didier Colau,2 Benoît Van den Eynde,2 Bernard Masereel,1 Johan Wouters,1 and Raphaël Frédérick1 1. Namur Drug Design and Discovery Center (ND3C), University of Namur, FUNDP, 61 Rue de Bruxelles, 5000 Namur, Belgium 2. Ludwig Institute for Cancer Research (LICR), Université Catholique de Louvain, 74 Avenue Hippocrate, 1200 Brussels, Belgium Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO1) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance, and IDO1 inhibition is an active area of drug development. Recently, the team of Benoit Van den Eynde (LICR, UCL, Belgium) has shown that tryptophan 2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is also expressed in many tumors and that this expression prevents tumor rejection by locally depleting tryptophan. In this communication, a detailed structure-activity study of a series of 3-(2-(pyridyl)ethenyl)indoles targeting TDO will be presented. This study led to the identification of a very potent, selective and orally available TDO inhibitor (LM10) which, upon systemic treatment, restored the ability of mice to reject TDO-expressing tumors. Our results thus describe a new mechanism of tumoral immune resistance based on TDO expression and establish proof-of-concept for the use of TDO inhibitors in cancer therapy.

AB - Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase (TDO): design, synthesis and preclinical evaluation of novel TDO inhibitors Eduard Dolusic1, Pierre Larrieu,2 Laurence Moineaux,1 Vincent Stroobant,2 Luc Pilotte,2 Didier Colau,2 Benoît Van den Eynde,2 Bernard Masereel,1 Johan Wouters,1 and Raphaël Frédérick1 1. Namur Drug Design and Discovery Center (ND3C), University of Namur, FUNDP, 61 Rue de Bruxelles, 5000 Namur, Belgium 2. Ludwig Institute for Cancer Research (LICR), Université Catholique de Louvain, 74 Avenue Hippocrate, 1200 Brussels, Belgium Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO1) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance, and IDO1 inhibition is an active area of drug development. Recently, the team of Benoit Van den Eynde (LICR, UCL, Belgium) has shown that tryptophan 2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is also expressed in many tumors and that this expression prevents tumor rejection by locally depleting tryptophan. In this communication, a detailed structure-activity study of a series of 3-(2-(pyridyl)ethenyl)indoles targeting TDO will be presented. This study led to the identification of a very potent, selective and orally available TDO inhibitor (LM10) which, upon systemic treatment, restored the ability of mice to reject TDO-expressing tumors. Our results thus describe a new mechanism of tumoral immune resistance based on TDO expression and establish proof-of-concept for the use of TDO inhibitors in cancer therapy.

M3 - Conference contribution

VL - OC01

SP - OC01

BT - Book of Abstracts, Emerging Targets and Treatments: Opportunities and Challenges for Drug Design, Ghent, 25 November 2011

ER -

Dolusic E, Larrieu P, Moineaux L, Stroobant V, Pilotte L, Colau D et al. coauthor on lecture: Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase (TDO): discovery of an orally active TDO inhibitor. In Book of Abstracts, Emerging Targets and Treatments: Opportunities and Challenges for Drug Design, Ghent, 25 November 2011: Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (MedChem 2011). Vol. OC01. 2011. p. OC01