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

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