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

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

  • Röhrig UF Swiss Institute of Bioinformatics, Molecular Modeling Group, Quartier Sorge - Bâtiment Génopode, CH-1015 Lausanne, Switzerland. Electronic address: ute.roehrig@isb-sib.ch.
  • Majjigapu SR 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.
  • Chambon M Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland. Electronic address: marc.chambon@epfl.ch.
  • Bron S Swiss Institute of Bioinformatics, Molecular Modeling Group, Quartier Sorge - Bâtiment Génopode, CH-1015 Lausanne, Switzerland. Electronic address: sylvian.bron@unil.ch.
  • Pilotte L 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.
  • Colau D 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.
  • Van den Eynde BJ 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.
  • Turcatti G Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland. Electronic address: gerardo.turcatti@epfl.ch.
  • Vogel P Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland. Electronic address: pierre.vogel@epfl.ch.
  • Zoete V Swiss Institute of Bioinformatics, Molecular Modeling Group, Quartier Sorge - Bâtiment Génopode, CH-1015 Lausanne, Switzerland. Electronic address: vincent.zoete@isb-sib.ch.
  • Michielin O 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.
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  • 2014-07-19
Published in:
  • European journal of medicinal chemistry. - 2014
Cancer immunotherapy
Enzyme inhibition
High throughput screening
In silico drug design
Indoleamine 2,3-dioxygenase
Molecular dynamics simulations
Structure–activity relationship
Tryptophan metabolism
Animals
Antifungal Agents
Dose-Response Relationship, Drug
Enzyme Inhibitors
High-Throughput Screening Assays
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase
Mice
Molecular Dynamics Simulation
Molecular Structure
Structure-Activity Relationship
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/78536
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