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

Research output: Contribution to conferencePoster

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Abstract

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
Original languageEnglish
PagesBook of Abstracts, Heterocycles in Bio-organic Chemistry, Riga, Latvia, 27 - 30 May 2013, PO129
Number of pages1
Publication statusPublished - 27 May 2013
EventHeterocycles in Bio-organic Chemistry - Riga, Latvia
Duration: 27 May 201330 May 2013

Conference

ConferenceHeterocycles in Bio-organic Chemistry
CountryLatvia
CityRiga
Period27/05/1330/05/13

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