Indole-pyridinyl-ethanones as novel inhibitors of indoleamine-2,3-dioxygenase (IDO), a promising target for anti-cancer immunotherapy

Eduard Dolusic, Pierre Larrieu, Sébastien Blanc, Laurence Moineaux, Delphine Colette, Graeme Fraser, Vincent Stroobant, Luc Pilotte, Didier Colaux, Johan Wouters, Bernard Masereel, Benoît Van den Eynde, Raphaël Frédérick

Research output: Contribution to conferencePoster


Immunotherapy is a promising novel and validated strategy for cancer therapy. It consists of the therapeutic vaccination of patients to stimulate their (natural) immune system against cancer cells. However, this approach showed a limited efficacy in vivo because cancer cells develop enzymatic mechanisms allowing tumours to resist or escape immune rejection. Among the enzymes involved, indoleamine 2,3-dioxygenase (IDO) was identified as a potential actor. IDO catalyses the rapid degradation of tryptophan (Trp) into N-formylkynurenine. This results in a local Trp depletion that severely affects T-cells proliferation and is thereby deeply immunosuppressive. Recently, the team of Prof. Van den Eynde demonstrated that many human tumours express IDO in a constitutive manner and that this expression allows cancer cells to escape immune rejection. IDO was thus clearly identified as an attractive target for the development of inhibitors. The recent elucidation of the three-dimensional structures of IDO, in complex with phenylimidazole and the cyanide ion (CN¯), provide important results for the structure-based drug discovery and design of novel IDO inhibitors. In the present work, we applied virtual screening for the discovery of new IDO inhibitors. As a result, five novel scaffolds with inhibitory potencies in the micromolar range were identified. Among these, the most promising candidate (1: IC50 = 65 µM) was selected and its inhibitory potency improved by chemical modifications. This led to a 7-fold improvement of the inhibitory potency of the hit selected. In this communication, the identification of 1, the synthesis and biological evaluation of a series of analogues as well as a modeling study explaining the SAR's will be presented.
Original languageEnglish
PagesBook of Abstracts, 25èmes Journées Franco-belges de Pharmacochimie, 19-20/05/11, Liège, P37, p. 62
Number of pages1
Publication statusPublished - 2011
EventJFB 2011. - Liege, Belgium
Duration: 19 May 2011 → …


ConferenceJFB 2011.
Period19/05/11 → …

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