Reversal of Tumoral Immune Resistance by Inhibition of Tryptophan 2,3-Dioxygenase (TDO): Design, Synthesis and Preclinical Evaluation of a Novel TDO Inhibitor.

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

Résultats de recherche: Contribution à un journal/une revueRevue de documentation

Résumé

Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase
(IDO1) is an important mechanism of peripheral immune tolerance
contributing to tumoral immune resistance,[1] and IDO1 inhibition is
an active area of drug development.[2] 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.[3] In this communication, a detailed
structure–activity study of a series of 3-(2-(pyridyl)ethenyl)indoles
as TDO inhibitors will be presented. This study led to the identification
of a potent and orally available TDO inhibitor (LM10) that,
upon systemic treatment, restored the ability of mice to reject TDOexpressing
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.[4,5]
langue originaleAnglais
Pages (de - à)371
Nombre de pages1
journalChemMedChem
étatPublié - 2012

Citer ceci

@article{896f2a216105466d8d5c227226fe3bf7,
title = "Reversal of Tumoral Immune Resistance by Inhibition of Tryptophan 2,3-Dioxygenase (TDO): Design, Synthesis and Preclinical Evaluation of a Novel TDO Inhibitor.",
abstract = "Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase(IDO1) is an important mechanism of peripheral immune tolerancecontributing to tumoral immune resistance,[1] and IDO1 inhibition isan active area of drug development.[2] Recently, the team of BenoitVan den Eynde (LICR, UCL, Belgium) has shown that tryptophan2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzingthe first step of tryptophan degradation, is also expressed inmany tumors and that this expression prevents tumor rejection bylocally depleting tryptophan.[3] In this communication, a detailedstructure–activity study of a series of 3-(2-(pyridyl)ethenyl)indolesas TDO inhibitors will be presented. This study led to the identificationof a potent and orally available TDO inhibitor (LM10) that,upon systemic treatment, restored the ability of mice to reject TDOexpressingtumors. Our results thus describe a new mechanism oftumoral immune resistance based on TDO expression and establishproof-of-concept for the use of TDO inhibitors in cancer therapy.[4,5]",
author = "Eduard Dolušić and Pierre Larrieu and Laurence Moineaux and Vincent Stroobant and Luc Pilotte and Didier Colaux and {Van den Eynde}, Beno{\^i}t and Bernard Masereel and Johan Wouters and Rapha{\"e}l Fr{\'e}d{\'e}rick",
year = "2012",
language = "English",
pages = "371",
journal = "ChemMedChem",
issn = "1860-7179",
publisher = "John Wiley and Sons Ltd",

}

Reversal of Tumoral Immune Resistance by Inhibition of Tryptophan 2,3-Dioxygenase (TDO): Design, Synthesis and Preclinical Evaluation of a Novel TDO Inhibitor. / Dolušić, Eduard; Larrieu, Pierre; Moineaux, Laurence; Stroobant, Vincent; Pilotte, Luc; Colaux, Didier; Van den Eynde, Benoît; Masereel, Bernard; Wouters, Johan; Frédérick, Raphaël.

Dans: ChemMedChem, 2012, p. 371.

Résultats de recherche: Contribution à un journal/une revueRevue de documentation

TY - JOUR

T1 - Reversal of Tumoral Immune Resistance by Inhibition of Tryptophan 2,3-Dioxygenase (TDO): Design, Synthesis and Preclinical Evaluation of a Novel TDO Inhibitor.

AU - Dolušić, Eduard

AU - Larrieu, Pierre

AU - Moineaux, Laurence

AU - Stroobant, Vincent

AU - Pilotte, Luc

AU - Colaux, Didier

AU - Van den Eynde, Benoît

AU - Masereel, Bernard

AU - Wouters, Johan

AU - Frédérick, Raphaël

PY - 2012

Y1 - 2012

N2 - Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase(IDO1) is an important mechanism of peripheral immune tolerancecontributing to tumoral immune resistance,[1] and IDO1 inhibition isan active area of drug development.[2] Recently, the team of BenoitVan den Eynde (LICR, UCL, Belgium) has shown that tryptophan2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzingthe first step of tryptophan degradation, is also expressed inmany tumors and that this expression prevents tumor rejection bylocally depleting tryptophan.[3] In this communication, a detailedstructure–activity study of a series of 3-(2-(pyridyl)ethenyl)indolesas TDO inhibitors will be presented. This study led to the identificationof a potent and orally available TDO inhibitor (LM10) that,upon systemic treatment, restored the ability of mice to reject TDOexpressingtumors. Our results thus describe a new mechanism oftumoral immune resistance based on TDO expression and establishproof-of-concept for the use of TDO inhibitors in cancer therapy.[4,5]

AB - Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase(IDO1) is an important mechanism of peripheral immune tolerancecontributing to tumoral immune resistance,[1] and IDO1 inhibition isan active area of drug development.[2] Recently, the team of BenoitVan den Eynde (LICR, UCL, Belgium) has shown that tryptophan2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzingthe first step of tryptophan degradation, is also expressed inmany tumors and that this expression prevents tumor rejection bylocally depleting tryptophan.[3] In this communication, a detailedstructure–activity study of a series of 3-(2-(pyridyl)ethenyl)indolesas TDO inhibitors will be presented. This study led to the identificationof a potent and orally available TDO inhibitor (LM10) that,upon systemic treatment, restored the ability of mice to reject TDOexpressingtumors. Our results thus describe a new mechanism oftumoral immune resistance based on TDO expression and establishproof-of-concept for the use of TDO inhibitors in cancer therapy.[4,5]

M3 - Literature review

SP - 371

JO - ChemMedChem

JF - ChemMedChem

SN - 1860-7179

ER -