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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Tryptophan Oxygenase
Indoles
Tryptophan
Molecular modeling
Tumors
Solubility
Degradation
Enzymes

Cite this

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 session presented at Heterocycles in Bio-organic Chemistry, Riga, Latvia.
Dolušić, Eduard ; Pilotte, Luc ; Moineaux, Laurence ; Larrieu, Pierre ; Stroobant, Vincent ; Colau, Didier ; Pochet, Lionel ; De Plaen, Etienne ; Uyttenhove, Catherine ; Van den Eynde, Benoît ; Wouters, Johan ; Masereel, Bernard ; Lanners, Steve ; Frédérick, Raphaël. / 3-ALKENYL INDOLES AS TRYPTOPHAN 2,3-DIOXYGENASE INHIBITORS FOR THE ENHANCEMENT OF CANCER IMMUNOTHERAPY. Poster session presented at Heterocycles in Bio-organic Chemistry, Riga, Latvia.1 p.
@conference{4d1fc42c865248918c4524a6d1fd3b9d,
title = "3-ALKENYL INDOLES AS TRYPTOPHAN 2,3-DIOXYGENASE INHIBITORS FOR THE ENHANCEMENT OF CANCER IMMUNOTHERAPY",
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.2We 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",
author = "Eduard Dolušić and Luc Pilotte and Laurence Moineaux and Pierre Larrieu and Vincent Stroobant and Didier Colau and Lionel Pochet and {De Plaen}, Etienne and Catherine Uyttenhove and {Van den Eynde}, Beno{\^i}t and Johan Wouters and Bernard Masereel and Steve Lanners and Rapha{\"e}l Fr{\'e}d{\'e}rick",
year = "2013",
month = "5",
day = "27",
language = "English",
pages = "Book of Abstracts, Heterocycles in Bio--organic Chemistry, Riga, Latvia, 27 -- 30 May 2013, PO129",
note = "Heterocycles in Bio-organic Chemistry ; Conference date: 27-05-2013 Through 30-05-2013",

}

Dolušić, E, Pilotte, L, Moineaux, L, Larrieu, P, Stroobant, V, Colau, D, Pochet, L, De Plaen, E, Uyttenhove, C, Van den Eynde, B, Wouters, J, Masereel, B, Lanners, S & Frédérick, R 2013, '3-ALKENYL INDOLES AS TRYPTOPHAN 2,3-DIOXYGENASE INHIBITORS FOR THE ENHANCEMENT OF CANCER IMMUNOTHERAPY' Heterocycles in Bio-organic Chemistry, Riga, Latvia, 27/05/13 - 30/05/13, pp. Book of Abstracts, Heterocycles in Bio-organic Chemistry, Riga, Latvia, 27 - 30 May 2013, PO129.

3-ALKENYL INDOLES AS TRYPTOPHAN 2,3-DIOXYGENASE INHIBITORS FOR THE ENHANCEMENT OF CANCER IMMUNOTHERAPY. / Dolušić, Eduard; Pilotte, Luc; Moineaux, Laurence; Larrieu, Pierre; Stroobant, Vincent; Colau, Didier; Pochet, Lionel; De Plaen, Etienne; Uyttenhove, Catherine; Van den Eynde, Benoît; Wouters, Johan; Masereel, Bernard; Lanners, Steve; Frédérick, Raphaël.

2013. Book of Abstracts, Heterocycles in Bio-organic Chemistry, Riga, Latvia, 27 - 30 May 2013, PO129 Poster session presented at Heterocycles in Bio-organic Chemistry, Riga, Latvia.

Research output: Contribution to conferencePoster

TY - CONF

T1 - 3-ALKENYL INDOLES AS TRYPTOPHAN 2,3-DIOXYGENASE INHIBITORS FOR THE ENHANCEMENT OF CANCER IMMUNOTHERAPY

AU - Dolušić, Eduard

AU - Pilotte, Luc

AU - Moineaux, Laurence

AU - Larrieu, Pierre

AU - Stroobant, Vincent

AU - Colau, Didier

AU - Pochet, Lionel

AU - De Plaen, Etienne

AU - Uyttenhove, Catherine

AU - Van den Eynde, Benoît

AU - Wouters, Johan

AU - Masereel, Bernard

AU - Lanners, Steve

AU - Frédérick, Raphaël

PY - 2013/5/27

Y1 - 2013/5/27

N2 - 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.2We 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

AB - 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.2We 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

M3 - Poster

SP - Book of Abstracts, Heterocycles in Bio-organic Chemistry, Riga, Latvia, 27 - 30 May 2013, PO129

ER -

Dolušić E, Pilotte L, Moineaux L, Larrieu P, Stroobant V, Colau D et al. 3-ALKENYL INDOLES AS TRYPTOPHAN 2,3-DIOXYGENASE INHIBITORS FOR THE ENHANCEMENT OF CANCER IMMUNOTHERAPY. 2013. Poster session presented at Heterocycles in Bio-organic Chemistry, Riga, Latvia.