Discovery of a novel and selective Indoleamine 2,3-Dioxygenase (IDO-1) inhibitor 3-(5-Fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (EOS200271/PF-06840003) and its characterization as a potential clinical candidate

Tumors use tryptophan-catabolizing enzymes such as indoleamine 2,3-dioxygenase (IDO-1) to induce an immunosuppressive environment. IDO-1 is induced in response to inflammatory stimuli and promotes immune tolerance through effector T-cell anergy and enhanced Treg function. As such, IDO-1 is a nexus f...

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Bibliographic Details
Main Authors: Crosignani, S, Bingham, P, Bottemanne, P, Cannelle, H, Cauwenberghs, S, Cordonnier, M, Dalvie, D, Deroose, F, Feng, JL, Gomes, B, Greasley, S, Kaiser, SE, Kraus, M, Négrerie, M, Maegley, K, Miller, N, Murray, BW, Schneider, M, Soloweij, J, Stewart, AE, Tumang, J, Torti, VR, Van Den Eynde, B, Wythes, M
Format: Journal article
Language:English
Published: American Chemical Society 2017
Description
Summary:Tumors use tryptophan-catabolizing enzymes such as indoleamine 2,3-dioxygenase (IDO-1) to induce an immunosuppressive environment. IDO-1 is induced in response to inflammatory stimuli and promotes immune tolerance through effector T-cell anergy and enhanced Treg function. As such, IDO-1 is a nexus for the induction of a key immunosuppressive mechanism and represents an important immunotherapeutic target in oncology. Starting from HTS hit 5, IDO-1 inhibitor 6 (EOS200271/PF-06840003) has been developed. The structure-activity relationship around 6 is described and rationalized using the X-ray crystal structure of 6 bound to human IDO-1, which shows that 6, differently from most of the IDO-1 inhibitors described so far, does not bind to the heme iron atom and has a novel binding mode. Clinical candidate 6 shows good potency in an IDO-1 human whole blood assay and also shows a very favorable ADME profile leading to favorable predicted human pharmacokinetic properties, including a predicted half-life of 16-19 h.