title: 1,2,3-Triazoles as inhibitors of indoleamine 2,3-dioxygenase 2 (IDO2).
abstract: Indoleamine 2,3-dioxygenase 2 (IDO2) is a potential therapeutic target for the treatment of diseases that involve immune escape such as cancer. In contrast to IDO1, only a very limited number of inhibitors have been described for IDO2 due to inherent difficulties in expressing and purifying a functionally active, soluble form of the enzyme. Starting from our previously discovered highly efficient 4-aryl-1,2,3-triazole IDO1 inhibitor scaffold, we used computational structure-based methods to design inhibitors of IDO2 which we then tested in cellular assays. Our approach yielded low molecular weight inhibitors of IDO2, the most active displaying an IC50 value of 51μM for mIDO2, and twofold selectivity over hIDO1. These compounds could be useful as molecular probes to investigate the biological role of IDO2, and could inspire the design of new IDO2 inhibitors.
authors.affiliation: Molecular Modeling Group, SIB Swiss Institute for Bioinformatics, CH-1015 Lausanne, Switzerland.
authors.forename: Ute F
authors.initials: UF
authors.lastname: Röhrig
authors.affiliation: Molecular Modeling Group, SIB Swiss Institute for Bioinformatics, CH-1015 Lausanne, Switzerland; Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Somi Reddy
authors.initials: SR
authors.lastname: Majjigapu
authors.affiliation: Molecular Modeling Group, SIB Swiss Institute for Bioinformatics, CH-1015 Lausanne, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Caldelari
authors.affiliation: Molecular Modeling Group, SIB Swiss Institute for Bioinformatics, CH-1015 Lausanne, Switzerland.
authors.forename: Nahzli
authors.initials: N
authors.lastname: Dilek
authors.affiliation: Ludwig Center for Cancer Research of the University of Lausanne, CH-1066 Epalinges, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Reichenbach
authors.affiliation: Molecular Modeling Group, SIB Swiss Institute for Bioinformatics, CH-1015 Lausanne, Switzerland.
authors.forename: Kelly
authors.initials: K
authors.lastname: Ascencao
authors.affiliation: Ludwig Center for Cancer Research of the University of Lausanne, CH-1066 Epalinges, Switzerland.
authors.forename: Melita
authors.initials: M
authors.lastname: Irving
authors.affiliation: Ludwig Center for Cancer Research of the University of Lausanne, CH-1066 Epalinges, Switzerland; Department of Oncology, University of Lausanne and Centre Hospitalier Universitaire Vaudois (CHUV), CH-1011 Lausanne, Switzerland.
authors.forename: George
authors.initials: G
authors.lastname: Coukos
authors.affiliation: Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland; Ludwig Center for Cancer Research of the University of Lausanne, CH-1066 Epalinges, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Vogel
authors.affiliation: Molecular Modeling Group, SIB Swiss Institute for Bioinformatics, CH-1015 Lausanne, Switzerland. Electronic address: Vincent.Zoete@sib.swiss.
authors.forename: Vincent
authors.initials: V
authors.lastname: Zoete
authors.affiliation: Molecular Modeling Group, SIB Swiss Institute for Bioinformatics, CH-1015 Lausanne, Switzerland; Ludwig Center for Cancer Research of the University of Lausanne, CH-1066 Epalinges, Switzerland; Department of Oncology, University of Lausanne and Centre Hospitalier Universitaire Vaudois (CHUV), CH-1011 Lausanne, Switzerland. Electronic address: Olivier.Michielin@sib.swiss.
authors.forename: Olivier
authors.initials: O
authors.lastname: Michielin
mesh_terms: D020134:Catalytic Domain; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D008970:Molecular Weight; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014230:Triazoles
keywords: Cancer immunotherapy; Cellular assays; Indoleamine 2,3-dioxygenase; Molecular modeling; Tryptophan metabolism