2. Academic Validation
  3. 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

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

  • J Med Chem. 2017 Dec 14;60(23):9617-9629. doi: 10.1021/acs.jmedchem.7b00974.
Stefano Crosignani 1,  Patrick Bingham 2,  Pauline Bottemanne 1,  Hélène Cannelle 1,  Sandra Cauwenberghs 1,  Marie Cordonnier 1,  Deepak Dalvie 2,  Frederik Deroose 3,  Jun Li Feng 2,  Bruno Gomes 1,  Samantha Greasley 2,  Stephen E Kaiser 2,  Manfred Kraus 2,  Michel Négrerie 4,  Karen Maegley 2,  Nichol Miller 2,  Brion W Murray 2,  Manfred Schneider 1,  James Soloweij 2,  Albert E Stewart 2,  Joseph Tumang 2,  Vince R Torti 2,  Benoit Van Den Eynde 5,  Martin Wythes 2
Affiliations

Affiliations

  • 1 iTeos Therapeutics , Rue des Frères Wright 29, 6041 Gosselies, Belgium.
  • 2 La Jolla Laboratories, Pfizer Global Research and Development , 10770 Science Center Drive, San Diego, California 92121, United States.
  • 3 Asclepia Outsourcing Solutions , Damvalleistraat 49, Destelbergen 9070, Belgium.
  • 4 Ecole Polytechnique, Unité Inserm 1182 UMR 7645 , Route de Saclay, Palaiseau 91128, France.
  • 5 Ludwig Institute for Cancer Research, Université Catholique de Louvain , 74 Avenue Hippocrate, 1200 Brussels, Belgium.
PMID: 29111717 DOI: 10.1021/acs.jmedchem.7b00974
Abstract

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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