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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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 originale	Anglais
Pages	Book of Abstracts, Heterocycles in Bio-organic Chemistry, Riga, Latvia, 27 - 30 May 2013, PO129
Nombre de pages	1
Etat de la publication	Publié - 27 mai 2013
Evénement	Heterocycles in Bio-organic Chemistry - Riga, Lettonie Durée: 27 mai 2013 → 30 mai 2013

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Une conférence	Heterocycles in Bio-organic Chemistry
Pays/Territoire	Lettonie
La ville	Riga
période	27/05/13 → 30/05/13

SDG des Nations Unies

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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 févr. 2012, Dans: 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, Dans: ChemMedChem. p. 371 1 p.
Résultats de recherche: Contribution à un journal/une revue › Revue de documentation › Revue par des pairs
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 août 2012, Dans: European Journal of Medicinal Chemistry. 54, p. 95-102 8 p.
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2 Terminé

tryptophane 2,3-dioxygénase
Wouters, J. (Responsable du Projet)
1/10/11 → 30/09/13
Projet: Recherche
Conception, synthèse et étude de modulateurs d'enzymes impliquées dans le métabolisme du tryptophane, et en particulier dans la voie de la kynurénine.
FREDERICK, R. (Responsable du Projet)
1/10/07 → 30/09/10
Projet: Recherche

Physico-chimie et caractérisation (PC2)
Wouters, J. (!!Manager) & Aprile, C. (!!Manager)
Plateforme technologique Caracterisation physico-chimiques
Equipement/installations: Plateforme technolgique

2 Participation à une conférence, un congrès

Heterocycles in Bio-organic Chemistry
Dolusic, E. (Poster)
27 mai 2013
Activité: Participation ou organisation d'un événement › Participation à une conférence, un congrès
EFMC-ISMC 2010 XXIst INTERNATIONAL SYMPOSIUM ON MEDICINAL CHEMISTRY
Dolusic, E. (Poster)
5 sept. 2010 → 9 sept. 2010
Activité: Participation ou organisation d'un événement › Participation à une conférence, un congrès

Mladi Ogulinac u ekipi koja je na tragu lijeka protiv raka
Dolusic, E.
24/02/12
1 élément de Couverture média
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USPJEH MLADOGA OGULINCA
Dolusic, E.
24/02/12
1 élément de Couverture média
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Ogulinac Eduard Dolušić nadomak otkriću lijeka protiv raka
Dolusic, E.
23/02/12
1 élément de Couverture média
Presse/Médias: Autre

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.
Molle, N. (Auteur)Wouters, J. (Promoteur), Dolusic, E. (Jury), Moineaux, L. (Jury), Fonder, G. (Jury) & Leherte, L. (Jury), 2012
Student thesis: Master types › Master en sciences chimiques

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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 présenté � Heterocycles in Bio-organic Chemistry, Riga, Lettonie.

@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, Lettonie, 27/05/13 - 30/05/13 p. 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 présenté � Heterocycles in Bio-organic Chemistry, Riga, Lettonie.

Résultats de recherche: Contribution à un événement scientifique (non publié) › Poster › Revue par des pairs

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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