Tryptophan 2,3-Dioxygenase (TDO) Inhibitors as Anticancer Immunomodulators

Eduard Dolusic, Pierre Larrieu, Laurence Moineaux, Vincent Strobant, Luc Pilotte, Didier Colau, Lionel Pochet, Etienne De Plaen, Catherine Uyttenhove, Benoît Van den Eynde, Johan Wouters, Bernard Masereel, Raphael Frédérick

Résultats de recherche: Contribution à un événement scientifique (non publié)Poster

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Résumé

Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance.1 IDO inhibition has been an active area of research in drug development for a number of years.2 Recently, our group has shown that tryptophan 2,3 dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is as well expressed in many tumors preventing their rejection by locally depleting tryptophan.3 The role of tryptophan catabolites was demonstrated by another group.4 Herein, we report the syntheses and structure-activity studies around a series of 3-(2-(pyridyl)ethenyl)indoles.5 Some 80 novel heterocyclic compounds were synthesized. Their TDO inhibitory potency was evaluated and rationalized by molecular modeling studies. The best candidate in terms of potency, selectivity, solubility and oral bioavailability was evaluated in a preclinical model in mice. Upon systemic treatment, the compound reversed TDO-mediated tumoral immune resistance.6 References This work was supported in part by FNRS-Télévie (7.4.543.07). 1) Uyttenhove, C., et al, Nat. Med. 2003, 9, 1269-1274. 2) Macchiarulo, A., et al, Amino Acids 2009, 37, 219-229; Röhrig, U. F., et al, J. Med. Chem. 2010, 53, 1172-1189. 3) Van den Eynde, B., et al, WO2010008427, 2010. 4) Opitz, C. A., et al, Nature 2011, 478, 197-203. 5) Dolusic, E., et al, J. Med. Chem. 2011, 54, 5320-5334. 6) Pilotte, L., et al, Proc. Natl. Acad. Sci. USA 2012, 109, 2497 - 2502.
langue originaleAnglais
PagesProgramme & Book of Abstracts, BOSS XIII, KU Leuven, Belgium, 15 - 20 July 2012, P292, p. 339
Nombre de pages1
étatPublié - 15 juil. 2012
EvénementBOSS XIII - 13th Belgian Organic Synthesis Symposium Louvain, 15 - 20 juillet 2012 - Leuven, Belgique
Durée: 15 juil. 201220 juil. 2012

Une conférence

Une conférenceBOSS XIII - 13th Belgian Organic Synthesis Symposium Louvain, 15 - 20 juillet 2012
PaysBelgique
La villeLeuven
période15/07/1220/07/12

Empreinte digitale

Tryptophan Oxygenase
Immunologic Factors
Tryptophan
Indoleamine-Pyrrole 2,3,-Dioxygenase
Heterocyclic Compounds
Molecular modeling
Tumors
Solubility
Amino Acids
Degradation
Enzymes
Pharmaceutical Preparations

Citer ceci

Dolusic, E., Larrieu, P., Moineaux, L., Strobant, V., Pilotte, L., Colau, D., ... Frédérick, R. (2012). Tryptophan 2,3-Dioxygenase (TDO) Inhibitors as Anticancer Immunomodulators. Programme & Book of Abstracts, BOSS XIII, KU Leuven, Belgium, 15 - 20 July 2012, P292, p. 339. Poster présenté � BOSS XIII - 13th Belgian Organic Synthesis Symposium Louvain, 15 - 20 juillet 2012, Leuven, Belgique.
Dolusic, Eduard ; Larrieu, Pierre ; Moineaux, Laurence ; Strobant, Vincent ; Pilotte, Luc ; Colau, Didier ; Pochet, Lionel ; De Plaen, Etienne ; Uyttenhove, Catherine ; Van den Eynde, Benoît ; Wouters, Johan ; Masereel, Bernard ; Frédérick, Raphael. / Tryptophan 2,3-Dioxygenase (TDO) Inhibitors as Anticancer Immunomodulators. Poster présenté � BOSS XIII - 13th Belgian Organic Synthesis Symposium Louvain, 15 - 20 juillet 2012, Leuven, Belgique.1 p.
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abstract = "Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance.1 IDO inhibition has been an active area of research in drug development for a number of years.2 Recently, our group has shown that tryptophan 2,3 dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is as well expressed in many tumors preventing their rejection by locally depleting tryptophan.3 The role of tryptophan catabolites was demonstrated by another group.4 Herein, we report the syntheses and structure-activity studies around a series of 3-(2-(pyridyl)ethenyl)indoles.5 Some 80 novel heterocyclic compounds were synthesized. Their TDO inhibitory potency was evaluated and rationalized by molecular modeling studies. The best candidate in terms of potency, selectivity, solubility and oral bioavailability was evaluated in a preclinical model in mice. Upon systemic treatment, the compound reversed TDO-mediated tumoral immune resistance.6 References This work was supported in part by FNRS-T{\'e}l{\'e}vie (7.4.543.07). 1) Uyttenhove, C., et al, Nat. Med. 2003, 9, 1269-1274. 2) Macchiarulo, A., et al, Amino Acids 2009, 37, 219-229; R{\"o}hrig, U. F., et al, J. Med. Chem. 2010, 53, 1172-1189. 3) Van den Eynde, B., et al, WO2010008427, 2010. 4) Opitz, C. A., et al, Nature 2011, 478, 197-203. 5) Dolusic, E., et al, J. Med. Chem. 2011, 54, 5320-5334. 6) Pilotte, L., et al, Proc. Natl. Acad. Sci. USA 2012, 109, 2497 - 2502.",
author = "Eduard Dolusic and Pierre Larrieu and Laurence Moineaux and Vincent Strobant and Luc Pilotte 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 Raphael Fr{\'e}d{\'e}rick",
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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 2012, 'Tryptophan 2,3-Dioxygenase (TDO) Inhibitors as Anticancer Immunomodulators', BOSS XIII - 13th Belgian Organic Synthesis Symposium Louvain, 15 - 20 juillet 2012, Leuven, Belgique, 15/07/12 - 20/07/12 p. Programme & Book of Abstracts, BOSS XIII, KU Leuven, Belgium, 15 - 20 July 2012, P292, p. 339.

Tryptophan 2,3-Dioxygenase (TDO) Inhibitors as Anticancer Immunomodulators. / Dolusic, Eduard; Larrieu, Pierre; Moineaux, Laurence; Strobant, Vincent; Pilotte, Luc; Colau, Didier; Pochet, Lionel; De Plaen, Etienne; Uyttenhove, Catherine; Van den Eynde, Benoît; Wouters, Johan; Masereel, Bernard; Frédérick, Raphael.

2012. Programme & Book of Abstracts, BOSS XIII, KU Leuven, Belgium, 15 - 20 July 2012, P292, p. 339 Poster présenté � BOSS XIII - 13th Belgian Organic Synthesis Symposium Louvain, 15 - 20 juillet 2012, Leuven, Belgique.

Résultats de recherche: Contribution à un événement scientifique (non publié)Poster

TY - CONF

T1 - Tryptophan 2,3-Dioxygenase (TDO) Inhibitors as Anticancer Immunomodulators

AU - Dolusic, Eduard

AU - Larrieu, Pierre

AU - Moineaux, Laurence

AU - Strobant, Vincent

AU - Pilotte, Luc

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 - Frédérick, Raphael

PY - 2012/7/15

Y1 - 2012/7/15

N2 - Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance.1 IDO inhibition has been an active area of research in drug development for a number of years.2 Recently, our group has shown that tryptophan 2,3 dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is as well expressed in many tumors preventing their rejection by locally depleting tryptophan.3 The role of tryptophan catabolites was demonstrated by another group.4 Herein, we report the syntheses and structure-activity studies around a series of 3-(2-(pyridyl)ethenyl)indoles.5 Some 80 novel heterocyclic compounds were synthesized. Their TDO inhibitory potency was evaluated and rationalized by molecular modeling studies. The best candidate in terms of potency, selectivity, solubility and oral bioavailability was evaluated in a preclinical model in mice. Upon systemic treatment, the compound reversed TDO-mediated tumoral immune resistance.6 References This work was supported in part by FNRS-Télévie (7.4.543.07). 1) Uyttenhove, C., et al, Nat. Med. 2003, 9, 1269-1274. 2) Macchiarulo, A., et al, Amino Acids 2009, 37, 219-229; Röhrig, U. F., et al, J. Med. Chem. 2010, 53, 1172-1189. 3) Van den Eynde, B., et al, WO2010008427, 2010. 4) Opitz, C. A., et al, Nature 2011, 478, 197-203. 5) Dolusic, E., et al, J. Med. Chem. 2011, 54, 5320-5334. 6) Pilotte, L., et al, Proc. Natl. Acad. Sci. USA 2012, 109, 2497 - 2502.

AB - Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance.1 IDO inhibition has been an active area of research in drug development for a number of years.2 Recently, our group has shown that tryptophan 2,3 dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is as well expressed in many tumors preventing their rejection by locally depleting tryptophan.3 The role of tryptophan catabolites was demonstrated by another group.4 Herein, we report the syntheses and structure-activity studies around a series of 3-(2-(pyridyl)ethenyl)indoles.5 Some 80 novel heterocyclic compounds were synthesized. Their TDO inhibitory potency was evaluated and rationalized by molecular modeling studies. The best candidate in terms of potency, selectivity, solubility and oral bioavailability was evaluated in a preclinical model in mice. Upon systemic treatment, the compound reversed TDO-mediated tumoral immune resistance.6 References This work was supported in part by FNRS-Télévie (7.4.543.07). 1) Uyttenhove, C., et al, Nat. Med. 2003, 9, 1269-1274. 2) Macchiarulo, A., et al, Amino Acids 2009, 37, 219-229; Röhrig, U. F., et al, J. Med. Chem. 2010, 53, 1172-1189. 3) Van den Eynde, B., et al, WO2010008427, 2010. 4) Opitz, C. A., et al, Nature 2011, 478, 197-203. 5) Dolusic, E., et al, J. Med. Chem. 2011, 54, 5320-5334. 6) Pilotte, L., et al, Proc. Natl. Acad. Sci. USA 2012, 109, 2497 - 2502.

M3 - Poster

SP - Programme & Book of Abstracts, BOSS XIII, KU Leuven, Belgium, 15 - 20 July 2012, P292, p. 339

ER -

Dolusic E, Larrieu P, Moineaux L, Strobant V, Pilotte L, Colau D et al.. Tryptophan 2,3-Dioxygenase (TDO) Inhibitors as Anticancer Immunomodulators. 2012. Poster présenté � BOSS XIII - 13th Belgian Organic Synthesis Symposium Louvain, 15 - 20 juillet 2012, Leuven, Belgique.