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

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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
Etat de la publicationPublié - 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
La villeLeuven

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