3-ALKENYL INDOLES AS TRYPTOPHAN 2,3-DIOXYGENASE INHIBITORS FOR THE ENHANCEMENT OF CANCER IMMUNOTHERAPY

Eduard Dolušić, Luc Pilotte, Laurence Moineaux, Pierre Larrieu, Vincent Stroobant, Didier Colau, Lionel Pochet, Etienne De Plaen, Catherine Uyttenhove, Benoît Van den Eynde, Johan Wouters, Bernard Masereel, Steve Lanners, Raphaël Frédérick

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Résumé

Recently, our group has shown that tryptophan 2,3 dioxygenase (TDO), a hepatic enzyme catalyzing the first step of tryptophan degradation, is expressed in many tumors, thereby contributing to tumoral immune resistance.1 The complementary role of tryptophan catabolites has been demonstrated by others.2
We set out to develop new, improved TDO inhibitors using as the starting point the only (unoptimized) series previously known in the literature.3
Herein, we describe the syntheses and structure-activity studies around a series of 3-alkenyl indoles and their derivatives.4 The TDO inhibitory potency was evaluated and rationalized by molecular modeling studies, while solubility, stability and oral bioavailability were determined for selected compounds. The most promising candidate was evaluated in a preclinical model in mice where, upon systemic treatment, it indeed reversed TDO-mediated tumoral immune resistance.5
langue originaleAnglais
PagesBook of Abstracts, Heterocycles in Bio-organic Chemistry, Riga, Latvia, 27 - 30 May 2013, PO129
Nombre de pages1
étatPublié - 27 mai 2013
EvénementHeterocycles in Bio-organic Chemistry - Riga, Lettonie
Durée: 27 mai 201330 mai 2013

Une conférence

Une conférenceHeterocycles in Bio-organic Chemistry
PaysLettonie
La villeRiga
période27/05/1330/05/13

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Contient cette citation

Dolušić, E., Pilotte, L., Moineaux, L., Larrieu, P., Stroobant, V., Colau, D., ... Frédérick, R. (2013). 3-ALKENYL INDOLES AS TRYPTOPHAN 2,3-DIOXYGENASE INHIBITORS FOR THE ENHANCEMENT OF CANCER IMMUNOTHERAPY. Book of Abstracts, Heterocycles in Bio-organic Chemistry, Riga, Latvia, 27 - 30 May 2013, PO129. Poster présenté � Heterocycles in Bio-organic Chemistry, Riga, Lettonie.