Rational Design of Indoleamine 2,3-Dioxygenase Inhibitors

Abstract

Indoleamine 2,3-dioxygenase (IDO) is an important therapeutic target for the treatment of diseases such as cancer that involve pathological immune escape. We have used the evolutionary docking algorithm EADock to design new inhibitors of this enzyme. First, we investigated the modes of binding of all known IDO inhibitors. On the basis of the observed docked conformations, we developed a pharmacophore model, which was then used to devise new compounds to be tested for IDO inhibition. We also used a fragment-based approach to design and to optimize small organic molecule inhibitors. Both approaches yielded several new low-molecular weight inhibitor scaffolds, the most active being of nanomolar potency in an enzymatic assay. Cellular assays confirmed the potential biological relevance of four different scaffolds.

Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase

“…We previously observed in a preclinical model that rejection of IDO1-expressing tumors was promoted by systemic treatment with an IDO1 inhibitor (4). The search for IDO1 inhibitors that can be used clinically is ongoing (7,(28)(29)(30). We show here that tumors also use another means to degrade tryptophan and resist immune rejection: they express TDO, the tryptophan-degrading enzyme normally expressed almost exclusively in the liver.…”

Fused Heterocyclic Compounds as Potent Indoleamine-2,3-dioxygenase 1 Inhibitors

“…13 residues (Y126, C129, and F163) present in the active site of IDO1 enzyme. 11,17,18 In our previous work, we successfully exploited these interactions and showed that halogen substituted aryl ring increased the inhibitory potencies of N′-hydroxyamidines. 8 We showed that the halogen substitution at the meta-and/or para-positions of the aryl ring of N′-hydroxyamidines had greater impact on their IDO1 inhibitory activity.…”

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

“…32 Indeed, this stabilization of the indole residue in Pocket A was already suggested by other groups in order to explain substrate binding as well as interaction of 1MT. In this position, the 3-pyridyl group is projected towards the entrance of the active site and is stabilized in the aromatic Pocket B through T-shape interactions with Phe163 and Phe226 (Fig.…”

“…yl-ethanone (7a) identified through a virtual screening procedure and possessing an IC 50 of 65 lM in the in vitro test, a fivefold improvement in potency (IC 50 = 13 lM) could be achieved by introducing a trifluoromethoxy group in the 5-position of the indole nucleus. Most small substituents around the indole moiety led to compounds of roughly equivalent potency, indicating room for further modifications but also a probable lack of close interactions of the inhibitor molecules with the IDO Pocket A interior as described by Rohrig et al 32 A similar generalization can be applied to the other aromatic moiety and its putative interactions with Pocket B of the IDO. Altogether, it seems no strong H-bond interactions with any of the hydrogen bonding residues in the IDO active site could be established.…”

“…32 Despite all these efforts, modestly potent 1MT (K i = 34 lM) 19 remains the only compound to have been passed into clinical trials as an IDO inhibitor so far. 33 This prompted us to search for new scaffolds that could be further optimized with the objective of identifying potent and selective IDO inhibitors.…”