New 4‐Amino‐1,2,3‐Triazole Inhibitors of Indoleamine 2,3‐Dioxygenase Form a Long‐Lived Complex with the Enzyme and Display Exquisite Cellular Potency

Abstract

Indoleamine-2,3 dioxygenase 1 (IDO1) has emerged as a central regulator of immune responses in both normal and disease biology. Due to its established role in promoting tumour immune escape, IDO1 has become an attractive target for cancer treatment. A novel series of highly cell potent IDO1 inhibitors based on a 4-amino-1,2,3-triazole core have been identified. Comprehensive kinetic, biochemical and structural studies demonstrate that compounds from this series have a noncompetitive kinetic mechanism of action with respect to the tryptophan substrate. In co-complex crystal structures, the compounds bind in the tryptophan pocket and make a direct ligand interaction with the haem iron of the porphyrin cofactor. It is proposed that these data can be rationalised by an ordered-binding mechanism, in which the inhibitor binds an apo form of the enzyme that is not competent to bind tryptophan. These inhibitors also form a very tight, long-lived complex with the enzyme, which partially explains their exquisite cellular potency. This novel series represents an attractive starting point for the future development of potent IDO1-targeted drugs.

High-resolution structures of inhibitor complexes of human indoleamine 2,3-dioxygenase 1 in a new crystal form

“…The first structure of human IDO1 was reported in 2006 at 2.3 Å resolution in a complex with the inhibitor 4-phenylimidazole (PI; Sugimoto et al, 2006). A large number of structures have been reported since then in complex with various compounds [Tojo et al, 2014; Peng et al, 2016; Wu et al, 2017; Lewis-Ballester et al, 2017; Crosignani et al, 2017; Alexandre et al, 2018;Nelp et al, 2018;PDB entry 6e35 (Northeast Structural Genomics Consortium, unpublished work)]. Most of these structures are in the same crystal form as the PI complex, although the resolution is often lower, with the lowest resolution of a published structure being 3.2 Å .…”

Mapping the Binding Trajectory of a Suicide Inhibitor in Human Indoleamine 2,3-Dioxygenase 1

“…However, the JK-Loop connecting the J-helix to the K-helix is completely disordered, as observed in other substrate-free complexes. 12,14–18 The F270 side chain moves down to the now empty Si site. In addition, a water molecule enters the Sa site and sits on top of the heme iron.…”

Synthesis, Docking and Biological Evaluation of a Novel Class of Imidazothiazoles as IDO1 Inhibitors

“…It must be acknowledged that the triazole moiety has been previously described by Röhrig et al [19] in IDO1 inhibitors and, more recently, in inhibitors selective for IDO2 [20]. In 2018 other triazole-displaying IDO1 inhibitors were reported [21]. In all the described examples, the nitrogen of the triazole ring makes a bond with the iron of the heme group.…”