Highlights at the gate of tryptophan catabolism: a review on the mechanisms of activation and regulation of indoleamine 2,3-dioxygenase (IDO), a novel target in cancer disease

Abstract

Indoleamine 2,3-dioxygenase (IDO) catalyzes the first and rate-limiting step of Kynurenine pathway along the major route of Tryptophan catabolism. The scientific interest in the enzyme has been growing since the observations of the involvement of IDO in the mechanisms of immune tolerance and in the mechanisms of tumor immuno-editing process. In view of this latter observation, in particular, preclinical studies of small molecule inhibitors of the enzyme have indicated the feasibility to thwart the immuno-editing process and to enhance the efficacy of current chemotherapeutic agents, supporting the notion that IDO is a novel target in cancer disease.This review covers the structural and conformational aspects of substrate recognition by IDO, including the catalytic mechanism and the so-far puzzling mechanisms of enzyme activation. Furthermore, we discuss the recent advances of medicinal chemistry in the field of IDO inhibitors.

Indol-2-yl ethanones as novel indoleamine 2,3-dioxygenase (IDO) inhibitors

“…Indeed, reduction of this group (18) or its removal altogether (19) led to inactive compounds thus confirming the requirement for an iron coordinating group (Table 4). Oxime 20 is endowed with an in vivo inhibitory potency similar to that of ketone 7a but surprisingly, this compound is not active in vitro.…”

“…Indeed, results from in vitro and in vivo studies have suggested an improvement of the efficacy of therapeutic vaccination or chemotherapy by concomitant administration of an IDO inhibitor thus highlighting IDO as an attractive target. 12,13,[15][16][17] Until recently, the best known IDO inhibitors 18 displayed affinities in the micromolar range and comprised mainly Trp derivatives such as 1-methyltryptophan (1MT) 19 (K i = 37 lM) or b-carbolines (K i $0.12 mM). 20 Other indole-based IDO inhibitors, such as brassinin 21,22 and methylthiohydantoin-tryptophan (MTH-Trp) 13 have been described.…”

Discovery and preliminary SARs of keto-indoles as novel indoleamine 2,3-dioxygenase (IDO) inhibitors

“…Until recently, the best known IDO inhibitors [15] displayed affinities in the micromolar range and comprised mainly Trp derivatives such as 1-methyl-L-tryptophan (1MT) [16] (K i w 34 mM) and b-carbolines [17]. In 2006, potent nanomolar inhibitors were isolated from marine invertebrate extracts [18,19] At the same time, new brassinin-based IDO inhibitors were published [20,21], the best having a K i of 12 mM.…”

Natural Product-Inspired Pyranonaphthoquinone Inhibitors of Indoleamine 2,3-Dioxygenase-1 (IDO-1)

“…This hypothesis, together with its expression in such a large number of human diseases has firmly established IDO-1 as an appealing drug target. [12][13][14][15][16][17][18] Furthermore, Zheng and co-workers have shown that murine melanoma cells, stably transformed with an IDO-1-silencing construct, exhibited a reduced capacity to form tumours compared with the unmodified parental melanoma cells when inoculated into recipient mice. [19] Moreover, tumours developing from the wild-type parental cells regressed when injected intra-tumourally with an anti-IDO siRNA.…”