Journal of Medicinal Chemistry p. 9617 - 9629 (2017)
Update date:2022-08-15
Topics:
Crosignani, Stefano
Bingham, Patrick
Bottemanne, Pauline
Cannelle, Hélène
Cauwenberghs, Sandra
Cordonnier, Marie
Dalvie, Deepak
Deroose, Frederik
Feng, Jun Li
Gomes, Bruno
Greasley, Samantha
Kaiser, Stephen E.
Kraus, Manfred
Négrerie, Michel
Maegley, Karen
Miller, Nichol
Murray, Brion W.
Schneider, Manfred
Soloweij, James
Stewart, Albert E.
Tumang, Joseph
Torti, Vince R.
Van Den Eynde, Benoit
Wythes, Martin
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.
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