1,2,3-Triazoles as inhibitors of indoleamine 2,3-dioxygenase 2 (IDO2)

Ute F Röhrig; Somi Reddy Majjigapu; Daniela Caldelari; Nahzli Dilek; Patrick Reichenbach; Kelly Ascencao; Melita Irving; George Coukos; Pierre Vogel; Vincent Zoete; Olivier Michielin

doi:10.1016/j.bmcl.2016.07.031

1,2,3-Triazoles as inhibitors of indoleamine 2,3-dioxygenase 2 (IDO2)

Bioorg Med Chem Lett. 2016 Sep 1;26(17):4330-3. doi: 10.1016/j.bmcl.2016.07.031. Epub 2016 Jul 16.

Authors

Affiliations

¹ Molecular Modeling Group, SIB Swiss Institute for Bioinformatics, CH-1015 Lausanne, Switzerland.
² 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.
³ Ludwig Center for Cancer Research of the University of Lausanne, CH-1066 Epalinges, Switzerland.
⁴ 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.
⁵ 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.
⁶ Molecular Modeling Group, SIB Swiss Institute for Bioinformatics, CH-1015 Lausanne, Switzerland. Electronic address: Vincent.Zoete@sib.swiss.
⁷ 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.

PMID: 27469130
DOI: 10.1016/j.bmcl.2016.07.031

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.

Keywords: Cancer immunotherapy; Cellular assays; Indoleamine 2,3-dioxygenase; Molecular modeling; Tryptophan metabolism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Catalytic Domain
Drug Design
Enzyme Activation / drug effects
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
Inhibitory Concentration 50
Molecular Weight
Triazoles / chemical synthesis*
Triazoles / chemistry
Triazoles / pharmacology

Substances

Enzyme Inhibitors
Indoleamine-Pyrrole 2,3,-Dioxygenase
Triazoles