Reversal of Tumoral Immune Resistance by Inhibition of Tryptophan 2,3-Dioxygenase (TDO): Design, Synthesis and Preclinical Evaluation of a Novel TDO Inhibitor.

Eduard Dolušić; Pierre Larrieu; Laurence Moineaux; Vincent Stroobant; Luc Pilotte; Didier Colaux; Benoît Van den Eynde; Bernard Masereel; Johan Wouters; Raphaël Frédérick

Reversal of Tumoral Immune Resistance by Inhibition of Tryptophan 2,3-Dioxygenase (TDO): Design, Synthesis and Preclinical Evaluation of a Novel TDO Inhibitor.

Eduard Dolušić, Pierre Larrieu, Laurence Moineaux, Vincent Stroobant, Luc Pilotte, Didier Colaux, Benoît Van den Eynde, Bernard Masereel, Johan Wouters, Raphaël Frédérick

Research output: Contribution to journal › Literature review › peer-review

Abstract

Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase
(IDO1) is an important mechanism of peripheral immune tolerance
contributing to tumoral immune resistance,[1] and IDO1 inhibition is
an active area of drug development.[2] Recently, the team of Benoit
Van den Eynde (LICR, UCL, Belgium) has shown that tryptophan
2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing
the first step of tryptophan degradation, is also expressed in
many tumors and that this expression prevents tumor rejection by
locally depleting tryptophan.[3] In this communication, a detailed
structure–activity study of a series of 3-(2-(pyridyl)ethenyl)indoles
as TDO inhibitors will be presented. This study led to the identification
of a potent and orally available TDO inhibitor (LM10) that,
upon systemic treatment, restored the ability of mice to reject TDOexpressing
tumors. Our results thus describe a new mechanism of
tumoral immune resistance based on TDO expression and establish
proof-of-concept for the use of TDO inhibitors in cancer therapy.[4,5]

Original language	English
Pages (from-to)	371
Number of pages	1
Journal	ChemMedChem
Publication status	Published - 2012

9 Poster
3 Article
1 Conference contribution
1 Paper
More
- 1 Literature review

3-ALKENYL INDOLES AS TRYPTOPHAN 2,3-DIOXYGENASE INHIBITORS FOR THE ENHANCEMENT OF CANCER IMMUNOTHERAPY
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., 27 May 2013, p. Book of Abstracts, Heterocycles in Bio-organic Chemistry, Riga, Latvia, 27 - 30 May 2013, PO129. 1 p.
Research output: Contribution to conference › Poster › peer-review

Open Access
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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.
Research output: Contribution to journal › Article › peer-review

Open Access
File
98 Downloads (Pure)
Tryptophan 2,3-Dioxygenase (TDO) Inhibitors as Anticancer Immunomodulators
Dolusic, E., Larrieu, P., Moineaux, L., Strobant, V., Pilotte, L., Colau, D., Pochet, L., De Plaen, E., Uyttenhove, C., Van den Eynde, B., Wouters, J., Masereel, B. & Frédérick, R., 15 Jul 2012, p. Programme & Book of Abstracts, BOSS XIII, KU Leuven, Belgium, 15 - 20 July 2012, P292, p. 339. 1 p.
Research output: Contribution to conference › Poster

File

2 Finished

tryptophane 2,3-dioxygénase
Wouters, J. (PI)
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. (PI)
1/10/07 → 30/09/10
Project: Research

Physical Chemistry and characterization(PC2)
Wouters, J. (Manager), Aprile, C. (Manager) & Fusaro, L. (Manager)
Technological Platform Physical Chemistry and characterization
Facility/equipment: Technological Platform

3 Participation in conference

Heterocycles in Bio-organic Chemistry
Dolusic, E. (Poster)
27 May 2013
Activity: Participating in or organising an event types › Participation in conference
BOSS XIII - 13th Belgian Organic Synthesis Symposium Louvain, 15 - 20 juillet 2012
Dolusic, E. (Poster)
15 Jul 2012
Activity: Participating in or organising an event types › Participation in conference
EFMC-ISMC 2010 XXIst INTERNATIONAL SYMPOSIUM ON MEDICINAL CHEMISTRY
Dolusic, E. (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
Dolusic, E.
24/02/12
1 item of Media coverage
Press/Media: Other
USPJEH MLADOGA OGULINCA
Dolusic, E.
24/02/12
1 item of Media coverage
Press/Media: Other
Ogulinac Eduard Dolušić nadomak otkriću lijeka protiv raka
Dolusic, E.
23/02/12
1 item of Media coverage
Press/Media: Other

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. (Author)Wouters, J. (Supervisor), Dolusic, E. (Jury), Moineaux, L. (Jury), Fonder, G. (Jury) & Leherte, L. (Jury), 2012
Student thesis: Master types › Master in Chemistry

Cite this

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title = "Reversal of Tumoral Immune Resistance by Inhibition of Tryptophan 2,3-Dioxygenase (TDO): Design, Synthesis and Preclinical Evaluation of a Novel TDO Inhibitor.",

abstract = "Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase(IDO1) is an important mechanism of peripheral immune tolerancecontributing to tumoral immune resistance,[1] and IDO1 inhibition isan active area of drug development.[2] Recently, the team of BenoitVan den Eynde (LICR, UCL, Belgium) has shown that tryptophan2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzingthe first step of tryptophan degradation, is also expressed inmany tumors and that this expression prevents tumor rejection bylocally depleting tryptophan.[3] In this communication, a detailedstructure–activity study of a series of 3-(2-(pyridyl)ethenyl)indolesas TDO inhibitors will be presented. This study led to the identificationof a potent and orally available TDO inhibitor (LM10) that,upon systemic treatment, restored the ability of mice to reject TDOexpressingtumors. Our results thus describe a new mechanism oftumoral immune resistance based on TDO expression and establishproof-of-concept for the use of TDO inhibitors in cancer therapy.[4,5]",

author = "Eduard Dolu{\v s}i{\'c} and Pierre Larrieu and Laurence Moineaux and Vincent Stroobant and Luc Pilotte and Didier Colaux and {Van den Eynde}, Beno{\^i}t and Bernard Masereel and Johan Wouters and Rapha{\"e}l Fr{\'e}d{\'e}rick",

year = "2012",

language = "English",

pages = "371",

journal = "ChemMedChem",

issn = "1860-7179",

publisher = "John Wiley and Sons Ltd",

}

TY - JOUR

T1 - Reversal of Tumoral Immune Resistance by Inhibition of Tryptophan 2,3-Dioxygenase (TDO): Design, Synthesis and Preclinical Evaluation of a Novel TDO Inhibitor.

AU - Dolušić, Eduard

AU - Larrieu, Pierre

AU - Moineaux, Laurence

AU - Stroobant, Vincent

AU - Pilotte, Luc

AU - Colaux, Didier

AU - Van den Eynde, Benoît

AU - Masereel, Bernard

AU - Wouters, Johan

AU - Frédérick, Raphaël

PY - 2012

Y1 - 2012

N2 - Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase(IDO1) is an important mechanism of peripheral immune tolerancecontributing to tumoral immune resistance,[1] and IDO1 inhibition isan active area of drug development.[2] Recently, the team of BenoitVan den Eynde (LICR, UCL, Belgium) has shown that tryptophan2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzingthe first step of tryptophan degradation, is also expressed inmany tumors and that this expression prevents tumor rejection bylocally depleting tryptophan.[3] In this communication, a detailedstructure–activity study of a series of 3-(2-(pyridyl)ethenyl)indolesas TDO inhibitors will be presented. This study led to the identificationof a potent and orally available TDO inhibitor (LM10) that,upon systemic treatment, restored the ability of mice to reject TDOexpressingtumors. Our results thus describe a new mechanism oftumoral immune resistance based on TDO expression and establishproof-of-concept for the use of TDO inhibitors in cancer therapy.[4,5]

AB - Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase(IDO1) is an important mechanism of peripheral immune tolerancecontributing to tumoral immune resistance,[1] and IDO1 inhibition isan active area of drug development.[2] Recently, the team of BenoitVan den Eynde (LICR, UCL, Belgium) has shown that tryptophan2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzingthe first step of tryptophan degradation, is also expressed inmany tumors and that this expression prevents tumor rejection bylocally depleting tryptophan.[3] In this communication, a detailedstructure–activity study of a series of 3-(2-(pyridyl)ethenyl)indolesas TDO inhibitors will be presented. This study led to the identificationof a potent and orally available TDO inhibitor (LM10) that,upon systemic treatment, restored the ability of mice to reject TDOexpressingtumors. Our results thus describe a new mechanism oftumoral immune resistance based on TDO expression and establishproof-of-concept for the use of TDO inhibitors in cancer therapy.[4,5]

M3 - Literature review

SN - 1860-7179

SP - 371

JO - ChemMedChem

JF - ChemMedChem

ER -

Reversal of Tumoral Immune Resistance by Inhibition of Tryptophan 2,3-Dioxygenase (TDO): Design, Synthesis and Preclinical Evaluation of a Novel TDO Inhibitor.

Abstract

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