title: Detailed analysis and follow-up studies of a high-throughput screening for indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors.
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.
authors.affiliation: Swiss Institute of Bioinformatics, Molecular Modeling Group, Quartier Sorge - Bâtiment Génopode, CH-1015 Lausanne, Switzerland. Electronic address: ute.roehrig@isb-sib.ch.
authors.forename: Ute F
authors.initials: UF
authors.lastname: Röhrig
authors.affiliation: 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: somireddy.majjigapu@epfl.ch.
authors.forename: Somi Reddy
authors.initials: SR
authors.lastname: Majjigapu
authors.affiliation: Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland. Electronic address: marc.chambon@epfl.ch.
authors.forename: Marc
authors.initials: M
authors.lastname: Chambon
authors.affiliation: Swiss Institute of Bioinformatics, Molecular Modeling Group, Quartier Sorge - Bâtiment Génopode, CH-1015 Lausanne, Switzerland. Electronic address: sylvian.bron@unil.ch.
authors.forename: Sylvian
authors.initials: S
authors.lastname: Bron
authors.affiliation: de Duve Institute and the Université catholique de Louvain, B-1200 Brussels, Belgium; Ludwig Institute for Cancer Research, B-1200 Brussels, Belgium. Electronic address: luc.pilotte@bru.licr.org.
authors.forename: Luc
authors.initials: L
authors.lastname: Pilotte
authors.affiliation: de Duve Institute and the Université catholique de Louvain, B-1200 Brussels, Belgium; Ludwig Institute for Cancer Research, B-1200 Brussels, Belgium. Electronic address: didier.colau@bru.licr.org.
authors.forename: Didier
authors.initials: D
authors.lastname: Colau
authors.affiliation: de Duve Institute and the Université catholique de Louvain, B-1200 Brussels, Belgium; Ludwig Institute for Cancer Research, B-1200 Brussels, Belgium. Electronic address: benoit.vandeneynde@bru.licr.org.
authors.forename: Benoît J
authors.initials: BJ
authors.lastname: Van den Eynde
authors.affiliation: Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland. Electronic address: gerardo.turcatti@epfl.ch.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Turcatti
authors.affiliation: Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland. Electronic address: pierre.vogel@epfl.ch.
authors.forename: Pierre
authors.initials: P
authors.lastname: Vogel
authors.affiliation: Swiss Institute of Bioinformatics, Molecular Modeling Group, Quartier Sorge - Bâtiment Génopode, CH-1015 Lausanne, Switzerland. Electronic address: vincent.zoete@isb-sib.ch.
authors.forename: Vincent
authors.initials: V
authors.lastname: Zoete
authors.affiliation: 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: olivier.michielin@isb-sib.ch.
authors.forename: Olivier
authors.initials: O
authors.lastname: Michielin
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; C576710:IDO1 protein, human; C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase
keywords: Cancer immunotherapy; Enzyme inhibition; High throughput screening; In silico drug design; Indoleamine 2,3-dioxygenase; Molecular dynamics simulations; Structure–activity relationship; Tryptophan metabolism