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

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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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 language	English
Pages	Book of Abstracts, Heterocycles in Bio-organic Chemistry, Riga, Latvia, 27 - 30 May 2013, PO129
Number of pages	1
Publication status	Published - 27 May 2013
Event	Heterocycles in Bio-organic Chemistry - Riga, Latvia Duration: 27 May 2013 → 30 May 2013

Conference

Conference	Heterocycles in Bio-organic Chemistry
Country/Territory	Latvia
City	Riga
Period	27/05/13 → 30/05/13

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Dolusic PO129 Riga 2013Accepted author manuscript, 721 KB
Abstract Dolusic Riga Bioheterocycles 2013 real

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Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase
Pilotte, L., Larrieu, P., Stroobant, V., Colau, D., Dolušić, E., Frédérick, R., De Plaen, E., Uyttenhove, C., Wouters, J., Masereel, B. & Van Den Eynde, B. J., 14 Feb 2012, In: Proceedings of the National Academy of Sciences of the United States of America. 109, 7, p. 2497-2502 6 p.
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Reversal of Tumoral Immune Resistance by Inhibition of Tryptophan 2,3-Dioxygenase (TDO): Design, Synthesis and Preclinical Evaluation of a Novel TDO Inhibitor.
Dolušić, E., Larrieu, P., Moineaux, L., Stroobant, V., Pilotte, L., Colaux, D., Van den Eynde, B., Masereel, B., Wouters, J. & Frédérick, R., 2012, In: ChemMedChem. p. 371 1 p.
Research output: Contribution to journal › Literature review › peer-review
Synthesis, crystal structures and electronic properties of isomers of chloro-pyridinylvinyl-1H-indoles
Moineaux, L., Laurent, S., Reniers, J., Dolusic, E., Galleni, M., Frère, J-M., Masereel, B., Frédérick, R. & Wouters, J., 1 Aug 2012, In: European Journal of Medicinal Chemistry. 54, p. 95-102 8 p.
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2 Finished

tryptophane 2,3-dioxygénase
Wouters, J.
1/10/11 → 30/09/13
Project: Research
Design, synthesis and study of enzyme modulators implicated in tryptophan metabolism and particularly in the kynurenin pathway
FREDERICK, R.
1/10/07 → 30/09/10
Project: Research

Physical Chemistry and characterization(PC2)
Johan Wouters (Manager) & Carmela Aprile (Manager)
Technological Platform Physical Chemistry and characterization
Facility/equipment: Technological Platform

2 Participation in conference

Heterocycles in Bio-organic Chemistry
Eduard Dolusic (Poster)
27 May 2013
Activity: Participating in or organising an event types › Participation in conference
EFMC-ISMC 2010 XXIst INTERNATIONAL SYMPOSIUM ON MEDICINAL CHEMISTRY
Eduard Dolusic (Poster)
5 Sept 2010 → 9 Sept 2010
Activity: Participating in or organising an event types › Participation in conference

Mladi Ogulinac u ekipi koja je na tragu lijeka protiv raka
Eduard Dolusic
24/02/12
1 item of Media coverage
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USPJEH MLADOGA OGULINCA
Eduard Dolusic
24/02/12
1 item of Media coverage
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Ogulinac Eduard Dolušić nadomak otkriću lijeka protiv raka
Eduard Dolusic
23/02/12
1 item of Media coverage
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Caractérisation enzymatique et structurale d'inhibiteurs indoliques de la tryptophane 2,3-dioxygénase.: Mémoire présenté pour l'obtention du grade académique de Master en Chimie "Chimie du Vivant et des Nanomatériaux" : Finalité Spécialisée.
Author: Molle, N., 2012
Supervisor: Wouters, J. (Supervisor), Dolusic, E. (Jury), Moineaux, L. (Jury), Fonder, G. (Jury) & Leherte, L. (Jury)
Student thesis: Master types › Master in Chemistry

Cite this

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. 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.

@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 Dolu{\v s}i{\'c} 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 = may,

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 et al.
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 conference › Poster › peer-review

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

T2 - Heterocycles in Bio-organic Chemistry

Y2 - 27 May 2013 through 30 May 2013

ER -

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

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