Tryptophan 2,3-dioxygenase (TDO) inhibitors. 3-(2-(pyridyl)ethenyl)indoles as potential anticancer immunomodulators

E. Dolušić, P. Larrieu, L. Moineaux, V. Stroobant, L. Pilotte, D. Colau, L. Pochet, B. Van Den Eynde, B. Masereel, J. Wouters, R. Frédérick

Research output: Contribution to journalArticle

Abstract

Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance. IDO inhibition is thus an active area of research in drug development. Recently, our group 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. Herein, we report a structure-activity study on a series of 3-(2-(pyridyl)ethenyl)indoles. More than 70 novel derivatives were synthesized, and their TDO inhibitory potency was evaluated. The rationalization of the structure-activity relationships (SARs) revealed essential features to attain high TDO inhibition and notably a dense H-bond network mainly involving His and Thr residues. Our study led to the identification of a very promising compound (58) displaying good TDO inhibition (K = 5.5 μM), high selectivity, and good oral bioavailability. Indeed, 58 was chosen for preclinical evaluation.
Original languageEnglish
Pages (from-to)5320-5334
Number of pages15
JournalJournal of Medicinal Chemistry
Volume54
Issue number15
DOIs
Publication statusPublished - 11 Aug 2011
EventBOSS XIII - 13th Belgian Organic Synthesis Symposium Louvain, 15 - 20 juillet 2012 - Leuven, Belgium
Duration: 15 Jul 201220 Jul 2012

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    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

    Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (Medchem 2011)

    Eduard Dolusic (Poster)

    25 Nov 2011

    Activity: Participating in or organising an event typesParticipation in conference

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    Mladi Ogulinac u ekipi koja je na tragu lijeka protiv raka

    Eduard Dolusic

    24/02/12

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    USPJEH MLADOGA OGULINCA

    Eduard Dolusic

    24/02/12

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    Ogulinac Eduard Dolušić nadomak otkriću lijeka protiv raka

    Eduard Dolusic

    23/02/12

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