2. Academic Validation
  3. Detailed analysis and follow-up studies of a high-throughput screening for indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors

Detailed analysis and follow-up studies of a high-throughput screening for indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors

  • Eur J Med Chem. 2014 Sep 12;84:284-301. doi: 10.1016/j.ejmech.2014.06.078.
Ute F Röhrig 1,  Somi Reddy Majjigapu 2,  Marc Chambon 3,  Sylvian Bron 4,  Luc Pilotte 5,  Didier Colau 6,  Benoît J Van den Eynde 7,  Gerardo Turcatti 8,  Pierre Vogel 9,  Vincent Zoete 10,  Olivier Michielin 11
Affiliations

Affiliations

  • 1 Swiss Institute of Bioinformatics, Molecular Modeling Group, Quartier Sorge - Bâtiment Génopode, CH-1015 Lausanne, Switzerland. Electronic address: [email protected].
  • 2 Swiss Institute of Bioinformatics, Molecular Modeling Group, Quartier Sorge - Bâtiment Génopode, CH-1015 Lausanne, Switzerland; Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland. Electronic address: [email protected].
  • 3 Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland. Electronic address: [email protected].
  • 4 Swiss Institute of Bioinformatics, Molecular Modeling Group, Quartier Sorge - Bâtiment Génopode, CH-1015 Lausanne, Switzerland. Electronic address: [email protected].
  • 5 de Duve Institute and the Université catholique de Louvain, B-1200 Brussels, Belgium; Ludwig Institute for Cancer Research, B-1200 Brussels, Belgium. Electronic address: [email protected].
  • 6 de Duve Institute and the Université catholique de Louvain, B-1200 Brussels, Belgium; Ludwig Institute for Cancer Research, B-1200 Brussels, Belgium. Electronic address: [email protected].
  • 7 de Duve Institute and the Université catholique de Louvain, B-1200 Brussels, Belgium; Ludwig Institute for Cancer Research, B-1200 Brussels, Belgium. Electronic address: [email protected].
  • 8 Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland. Electronic address: [email protected].
  • 9 Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland. Electronic address: [email protected].
  • 10 Swiss Institute of Bioinformatics, Molecular Modeling Group, Quartier Sorge - Bâtiment Génopode, CH-1015 Lausanne, Switzerland. Electronic address: [email protected].
  • 11 Swiss Institute of Bioinformatics, Molecular Modeling Group, Quartier Sorge - Bâtiment Génopode, CH-1015 Lausanne, Switzerland; Department of Oncology, University of Lausanne and Centre Hospitalier Universitaire Vaudois (CHUV), CH-1011 Lausanne, Switzerland; Ludwig Center for Cancer Research of the University of Lausanne, CH-1015 Lausanne, Switzerland. Electronic address: [email protected].
PMID: 25036789 DOI: 10.1016/j.ejmech.2014.06.078
Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulator of immune responses and therefore an important therapeutic target for the treatment of diseases that involve pathological immune escape, such as Cancer. Here, we describe a robust and sensitive high-throughput screen (HTS) for IDO1 inhibitors using the Prestwick Chemical Library of 1200 FDA-approved drugs and the Maybridge HitFinder Collection of 14,000 small molecules. Of the 60 hits selected for follow-up studies, 14 displayed IC50 values below 20 μM under the secondary assay conditions, and 4 showed an activity in cellular tests. In view of the high attrition rate we used both experimental and computational techniques to identify and to characterize compounds inhibiting IDO1 through unspecific inhibition mechanisms such as chemical reactivity, redox cycling, or aggregation. One specific IDO1 Inhibitor scaffold, the imidazole Antifungal agents, was chosen for rational structure-based lead optimization, which led to more soluble and smaller compounds with micromolar activity.

Keywords

Cancer immunotherapy; Enzyme inhibition; High throughput screening; In silico drug design; Indoleamine 2,3-dioxygenase; Molecular dynamics simulations; Structure–activity relationship; Tryptophan metabolism.

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