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
  • 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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