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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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-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.
Original languageEnglish
PagesProgramme & Book of Abstracts, BOSS XIII, KU Leuven, Belgium, 15 - 20 July 2012, P292, p. 339
Number of pages1
Publication statusPublished - 15 Jul 2012
EventBOSS XIII - 13th Belgian Organic Synthesis Symposium Louvain, 15 - 20 juillet 2012 - Leuven, Belgium
Duration: 15 Jul 201220 Jul 2012

Conference

ConferenceBOSS XIII - 13th Belgian Organic Synthesis Symposium Louvain, 15 - 20 juillet 2012
CountryBelgium
CityLeuven
Period15/07/1220/07/12

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    • 3 Participation in conference

    Heterocycles in Bio-organic Chemistry

    Eduard Dolusic (Poster)

    27 May 2013

    Activity: Participating in or organising an event typesParticipation in conference

    BOSS XIII - 13th Belgian Organic Synthesis Symposium Louvain, 15 - 20 juillet 2012

    Eduard Dolusic (Poster)

    15 Jul 2012

    Activity: Participating in or organising an event typesParticipation in conference

    EFMC-ISMC 2010 XXIst INTERNATIONAL SYMPOSIUM ON MEDICINAL CHEMISTRY

    Eduard Dolusic (Poster)

    5 Sep 20109 Sep 2010

    Activity: Participating in or organising an event typesParticipation in conference

    Cite this

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