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Cancer II pp 371-371 | Cite as

Inhibitors of the Kynurenine Pathway

  • Ute F. RöhrigEmail author
  • Vincent ZoeteEmail author
  • Olivier MichielinEmail author
Part of the Topics in Medicinal Chemistry book series (TMC, volume 28)

Abstract

A central role in the immune escape of tumors has been attributed to the kynurenine pathway of tryptophan metabolism, leading to the depletion of tryptophan and the production of different bioactive metabolites. The first and rate-limiting step in this pathway is catalyzed by the phylogenetically unrelated enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO), which have both been shown to be expressed in different cancers. Intense efforts in academia and in pharmaceutical companies to develop novel inhibitor scaffolds yielded a few compounds currently undergoing clinical trials. Here, we review the most significant compounds in the field and discuss potential issues in the development of kynurenine pathway inhibitors for cancer therapy.

Keywords

Immuno-oncology Indoleamine 2,3-dioxygenase Kynurenine pathway Tryptophan 2,3-dioxygenase Tryptophan metabolism 

1 Introduction

Cancer immunotherapy is a rapidly evolving field [1], which has generated much excitement among scientists and cancer patients over the last years because of the efficacy of immune checkpoint inhibitors [2], chimeric antigen receptor T-cell therapy [3], and adoptive cell therapy with tumor infiltrating lymphocytes [4]. These promising new therapies, as well as more traditional approaches such as vaccination, chemotherapy, or radiotherapy could benefit from the combination with a strategy to overcome tumor-induced immunosuppression [5, 6, 7]. A central role in immune escape is played by the kynurenine pathway of L-tryptophan (L-Trp) metabolism (Fig. 1) [8, 9, 10, 11]. This pathway, which has been estimated to be responsible for more than 99% of L-Trp degradation in humans [12, 13], leads to the depletion of L-Trp and to the production of kynurenine metabolites and causes local immunosuppression [14, 15, 16, 17]. The pathway is not only involved in the immune system, for example, in establishing immune tolerance versus the fetus during pregnancy [18] and in the response to infections [19], but it also influences the nervous system and plays a major role in neurological and mental disorders [20, 21]. The first and rate-limiting step in the kynurenine pathway is the oxidation of L-Trp to N-formylkynurenine (NFK, Fig. 1). This reaction is catalyzed by two evolutionarily unrelated heme enzymes, tryptophan 2,3-dioxygenase (TDO, EC 1.13.11.11) and indoleamine 2,3-dioxygenase 1 (IDO1, EC 1.13.11.52). TDO is a homotetrameric enzyme, upregulated by glucocorticoid hormones and the availability of L-Trp, constitutively expressed in the liver, and responsible for regulating systemic L-Trp levels [16]. IDO1 on the other hand is a monomeric enzyme induced by interferon gamma and expressed in different cell types and tissues [16, 22]. IDO1 has first been implicated in tumoral immune resistance in 2003 [23], a discovery that initiated a very active field of drug development. The implication of TDO in similar mechanisms has been described more recently [24, 25]. The role of the IDO1 paralogue indoleamine 2,3-dioxygenase 2 (IDO2) [26, 27, 28] remains less clear due to ambiguous experimental findings. IDO2 shows a very low affinity for L-Trp and a low turnover rate [29]. Different issues have hampered biological studies of L-Trp metabolism, such as: (1) difficulties in obtaining gene knockout mice lacking both IDO1 and IDO2 [30], (2) antibody reagents against murine IDO1 lacking specificity [31, 32], and (3) the widespread use of high concentrations of the very unspecific IDO1 inhibitor 1-methyl-tryptophan (1MT), which has been shown to additionally induce IDO1 [24] and to be contaminated with L-Trp [33].
Fig. 1

Kynurenine pathway

Here, we concentrate on the description of small molecule inhibitors of the first step of L-Trp metabolism, namely of IDO1, TDO, and IDO2, as these are the main targets for cancer therapy.

2 Indoleamine 2,3-Dioxygenase 1 Inhibitors

IDO1 (EC 1.13.11.52) is the most well-established target in the kynurenine pathway for cancer immunotherapy [22]. It has been shown to be expressed by tumor cells in order to escape a potentially effective immune response [14, 23, 34, 35], and high IDO1 expression is associated with poor prognosis in different cancer types [36]. In vitro and in vivo studies demonstrate that administration of an IDO1 inhibitor improves the efficacy of therapeutic vaccination, chemotherapy, or radiation therapy [23, 37, 38, 39, 40].

IDO1 is a heme enzyme that catalyzes the oxidation of L-Trp to NFK by the incorporation of molecular oxygen and the cleavage of the pyrrole ring of the substrate. The crystal structures of human IDO1 [41, 42, 43] show one binding pocket in the distal heme site (Pocket A, Fig. 2a), connected to a second pocket towards the entrance of the active site (Pocket B, Fig. 2a) [44]. The “height” of the A pocket varies among different X-ray structures, as evident from Fig. 2a–d.
Fig. 2

X-ray structures of indoleamine 2,3-dioxygenase 1 (IDO1) [41, 42, 43]. Only the active site is shown, displaying the protein in surface representation, heme and His346 in stick representation, and the ligand in ball and stick representation. Heteroatoms are colored as follows: blue (nitrogen), red (oxygen), yellow (sulfur), green (chloride), and orange (iron). Hydrogen bonds are shown as thin orange lines. (a) Structure 2D0T bound to 4PI (7) and two molecules of CHES buffer (displayed in stick representation) [41]. The A pocket above the heme distal site and the B pocket towards the entrance of the active site [44] are highlighted. (b) Structure 4PK5 bound to compound 38 [42]. (c) Low resolution (3.45 Å) structure 4PK6 bound to an imidazothiazole derivative [42]. (d) Structure 5EK4 bound to compound 15, an analog of GDC-0919 [43]

Intense efforts in academia and in the pharmaceutical industry to develop IDO1 inhibitors led to at least three compounds in clinical trials so far. The most advanced compound, at the time of writing, was the hydroxyamidine 18 (INCB024360, epacadostat) [38, 45, 46, 47] developed by Incyte Corporation, which had been tested in combination with different other cancer therapies and partners in clinical trials up to phase III. A second compound in phase I clinical studies at the time of writing is the imidazole GDC-0919 (formerly known as NLG919 or RG6078, structure not disclosed) [48, 49] discovered by NewLink Genetics and developed together with Genentech. iTeos Therapeutics [50, 51, 52, 53] in partnership with Pfizer initiated a phase I study with compound PF-06840003 (undisclosed structure) for patients with malignant gliomas (NCT02764151).

In addition to academic groups, the pharma companies Amgen [54], Bristol-Myers Squibb [55, 56, 57, 58], Curadev [59, 60, 61] (partnering with Roche), Dainippon Sumitomo Pharma Corporation [42], Flexus Biosciences [62, 63, 64, 65] (acquired by Bristol-Myers Squibb in 2015), IOmet Pharma [66, 67, 68, 69, 70] (acquired by Merck & Co. in 2016), Merck Group [71], Redx Pharma [72, 73], and Vertex Pharmaceuticals [74] have all reported work on the development of IDO1 inhibitors.

IDO1 inhibitory properties have been attributed to thousands of compounds, but many of them may act through unspecific mechanisms [75]. Here, we limit ourselves to discuss the most relevant and novel scaffolds. A complete review of IDO1 inhibitors described before February 2015 can be found in a recent review [75]. In the following figures, ligands are shown in their putative binding conformation to IDO1 according to Fig. 2 whenever possible, with the heme-iron facing group in the lower left, the A-pocket binding group in the upper left, and the B-pocket binding group extending to the right.

2.1 1-Methyl-Tryptophan

The most widely used IDO1 inhibitor in biological studies up to date is 1MT [76] despite its moderate activity (Ki = 19–53 μM) [39, 76, 77, 78, 79, 80]. 1MT, like tryptophan, is a chiral compound, and it has been shown that only the L enantiomer (1, Fig. 3) inhibits the enzymatic activity of IDO1 in vitro [77, 78] However, based on the findings that the D enantiomer (2, Fig. 3) was more efficacious as an anticancer agent in vivo [78], NewLink Genetics initiated clinical trials with D-1MT (indoximod) as anticancer agent. As a possible explanation of the better in vivo activity of D-1MT it was later suggested that D-1MT preferentially inhibits the IDO1 paralogue IDO2 [27], but this finding was rejected by subsequent studies [82, 83, 84, 85]. Therefore, the mechanism of action of D-1MT as a kynurenine pathway inhibitor is still under debate [24, 34, 86, 87, 88, 89]. Additional complications in interpreting experimental data generated with the tool compound 1MT may arise from the facts that D-1MT has been shown to induce IDO1 expression [24] and that L-1MT can be substantially contaminated with L-Trp [33].
Fig. 3

IDO1 inhibitors based on the indole scaffold. L-1MT (1), D-1MT (2), keto-indole (3) [81], oxindole (4) [66], indole-2-carboxamide (5) [67], and 6-fluoro indole (6) [53]

At present, it is clear that D-1MT is not a human IDO1 inhibitor. The use of L-1MT as a tool compound for IDO1 inhibition should be avoided due to its low activity and specificity, and due to the availability of more active and selective inhibitors.

2.2 Indoles

IDO1 inhibitors known before the implication of this enzyme in tumoral immune resistance were of moderate micromolar activity [90]. Many of these were analogs of the substrate L-Trp or its indole scaffold [76, 77, 91, 92, 93, 94]. However, as L-Trp itself shows only a moderate affinity for IDO1 (Kd = 290–320 μM) [41, 95], also most of its analogs were only moderately active towards IDO1. Double-digit micromolar activities were reached by some keto indoles discovered by virtual screening (3, Fig. 3) [81, 96].

IOmet Pharma (now Merck & Co.) tested 3-substituted indoles and oxindoles for IDO1 and TDO inhibition (Fig. 3) [66]. Although none of the compounds displayed an enzymatic IC50 value below 100 μM on IDO1, some were low micromolar IDO1 inhibitors in a cellular context with at least tenfold selectivity over TDO (4), while other compounds were selective for TDO (Sect. 3.1). The observation that compounds display better cellular IC50 values than enzymatic IC50 values has been frequently observed for IDO1 and could be due to off-target effects or the artificial reducing cofactors routinely used in the enzymatic assay [75].

In the following, IOmet Pharma described a large series of indole-2-carboxamides [67]. Many compounds displayed cellular IC50 values below 3 μM on hIDO1 and more than tenfold selectivity with respect to TDO. For a few compounds, an enzymatic IC50 value below 10 μM was cited (5). Interestingly, the indole-2-carboxamide scaffold has also been shown to possess high antitubercular activity in an animal model of tuberculosis [97, 98], and IDO1 has been implicated in tuberculosis infection [99].

More recently, iTeos Therapeutics described a series of 3-indol-3-yl-pyrrolidine-2,5-diones (succinimides) with potent IDO1 inhibitory properties [53]. The most potent compound (6) in its enantiopure R form displayed an enzymatic IC50 value of 120 nM, nanomolar cellular activities, an IC50 value of 3 μM in a human whole blood assay, an EC50 value of 74 nM in an IDO1-dependent cellular T-cell proliferation assay, in vivo reduction of kynurenine levels in the blood of healthy mice of up to 68% (100 mg/kg), as well as in vivo inhibition of tumor growth in different cancer models.

In summary, it seems to be challenging to develop potent selective IDO1 inhibitors based on the indole scaffold. At the time of writing, only iTeos Therapeutics succeeded in developing a nanomolar indole IDO1 inhibitor.

2.3 Imidazoles

The known heme-binder 4-phenylimidazole (4PI, 7, Fig. 4) was described as an IDO1 inhibitor in 1989 [100] and gained attention due to its co-crystallization with IDO1 in 2006 (Fig. 2a) [41]. A structure-based approach led to 4PI derivatives that were up to tenfold more potent than the parent compound 8 [101]. Fungistatic drugs of the 1-substituted imidazole type, such as miconazole and econazole (9), were discovered in two independent screens to be active against IDO1, while similar 1,2,4-triazole drugs such as fluconazole were completely inactive [102, 103]. Structure-based modifications of the 1-substituted imidazole antifungal scaffold led to more soluble but less potent compounds (10) [103].
Fig. 4

IDO1 inhibitors with imidazole scaffold. 4-phenylimidazole (4PI, 7) [100, 101], 4PI derivative (8) [101], econazole (9) [102, 103], derivative of fungistatic imidazoles (10) [103], disubstituted imidazoles (11, 12) [104], 4PI derivative (13) [105], and fused imidazole-isoindoles (14, 15, 16, 17) [71, 106]. Stereocenters discussed in the main text are marked by an asterisk

Fallarini and coworkers created a virtual library of 1,5- and 4,5-disubstituted imidazoles and selected 25 compounds for synthesis and evaluation [104]. While the 1,5-disubstituted imidazoles were inactive with one exception (11), the best 4,5-disubstituted imidazoles displayed low micromolar enzymatic and cellular IC50 values (12). However, the presence of bulky substituents next to the heme-iron binding imidazole nitrogen should sterically hinder their direct heme binding, so it is not clear how they bind to IDO1.

NewLink Genetics developed further 4-substituted phenylimidazoles with nanomolar potency but a low ligand efficiency, because they featured a long extension into the B pocket (13) [105]. Fusion of the two aromatic rings of 4PI by an aliphatic carbon atom to yield imidazo-isoindoles (14), however, strongly enhanced potency with less impact on efficiency [106]. Two compounds of this series (14, 15) were tested in vivo for antitumor activity in mouse models of colorectal, bladder, mammary, and lung cancer as single agents or in combination with other chemotherapies. These tests showed that both compounds had a significant antitumor activity either as single agent or in combination therapy, leading to a significantly reduced rate of tumor growth and improved survival time [106]. Based on these results, it is likely that the clinical candidate GDC-0919 has a structure similar to compounds 14, 15. These compounds contain two asymmetric carbon atoms, marked by asterisks in Fig. 4, leading to four stereoisomers. For compound 14, it was found that the S-isomers of the carbon atom in the tricyclic scaffold were responsible for the nanomolar potency of the mixture of stereoisomers [106].

The pioneering work of NewLink Genetics stimulated other groups to work on the imidazole scaffold. Peng and coworkers evaluated some of the NewLink Genetics compounds and new analogs and provided IDO1-bound X-ray structures for three imidazole-isoindole derivatives and one pyridine analog (Fig. 2d) [43]. The most potent compound described in this work, which corresponds to compound 15 (Fig. 4) [106], was shown to display an enzymatic IC50 value of 19 nM and a cellular IC50 value of 55 nM. Its X-ray structure (PDB ID: 5EK4, Fig. 2d) revealed a hydrogen bond from its hydroxy group to the heme propionate, and the placement of the cyclohexyl group in the B pocket [43]. Here, the A pocket is much higher than in the 4PI-bound structure (Fig. 2a), but this additional volume is apparently neither filled by the ligand nor by solvent molecules. The parent compound without fluoro substituent (14), which displayed an enzymatic IC50 value of 38 nM and a cellular IC50 value of 61 nM, was investigated in more detail regarding the activity of its stereoisomers, and it was found that the individual enzymatic IC50 values of the four stereoisomers were 20 nM, 29 nM, 2.4 μM, and >10 μM [43]. Again, the S-isomers of the carbon atom in the tricyclic scaffold were found to be responsible for the nanomolar potency of the mixtures of stereoisomers.

Merck Group patented a series of related enantiopure tricyclic imidazo-isoindole compounds of high enzymatic potency (16, 17, Fig. 4, IC50 values < 100 nM) [71], finding the same preference for the S-isomers.

In summary, the phenylimidazole scaffold provides a popular and promising starting point for the development of IDO1 inhibitors. Its binding mode to the active site is known through X-ray crystallography [41, 43], it does not show promiscuous enzyme inhibition, rational modifications have been shown to be feasible, and interpretable structure–activity relationships are observed. The fact that 4PI and the fungistatic imidazoles inhibit various heme enzymes suggests that specificity for IDO1 needs to be achieved through optimized interactions with IDO1, for example, through molecular recognition by the B pocket. Selective TDO (Sect. 3.2) and dual IDO1/TDO inhibitors (Sect. 4.1) based on this scaffold have also been described.

2.4 N-Hydroxyamidines and Structurally Related Compounds

In 2009, Incyte Corporation reported N-hydroxyamidines as potent, reversible, competitive IDO1 inhibitors (Fig. 5) [45]. The most potent compound of this series, compound 19, displayed enzymatic and cellular IC50 values of 67 and 19 nM, suppressed kynurenine generation in vivo, and inhibited melanoma growth in a mouse model [45]. Modeling of the binding of 19 to IDO1 predicted that the oxygen of the hydroxyamidine binds to the heme iron, and that the amidine adopts a cis conformation. The phenyl ring was placed inside the A pocket, producing a tight fit, while the amino substituent on the furazan ring could form a hydrogen bond to the propanoic acid group on the heme ring [45]. The clinical candidate (18, epacadostat, CAS# 1204669-58-8) belongs to a further optimized series of N-hydroxyamidines with extension to the B pocket [107, 109]. Epacadostat was shown to inhibit IDO1 in enzymatic (IC50 = 72 nM) and in cellular tests (IC50 = 7.1 nM), to suppress Trp catabolism in vivo, to impede tumor growth, and not to inhibit IDO2, TDO, tryptophan transport, or a panel of 50 other proteins [38, 46].
Fig. 5

IDO1 inhibitors based on the N-hydroxyamidine and related scaffolds. Epacadostat (18) [107], N-hydroxyamidine (19) [45], nitrobenzofurazan N-hydroxyamidine (20) [108], N-hydroxyamidines (21, 22) [62], N-phenylamides (23, 24) [65], N-cyclohexylamide (25) [65], further modified N-phenylamides (26, 27) [63], benzamide (28) [64], phenylurea (29) [64], aniline (30) [64], and 2-phenyl-propanamide (31) [64]

Nitrobenzofurazan derivatives of the N-hydroxyamidine scaffold (20) [108] showed very good activities in enzymatic and cellular tests but a lower ligand efficiency than the Incyte compound 19. The described compounds were strongly selective for IDO1 over TDO by factors of 200–1,700.

Flexus Biosciences successfully modified Incyte’s N-hydroxyamidine scaffold first by simplifying the presumed B-pocket extension of the N-hydroxyamidines without the furazan ring and preserving nanomolar potencies (21, 22) [62]. Later, they replaced the N-hydroxyamidine group by a simple amide function and to obtain a large number of analogs with cellular IC50 values below 50 nM (23, 24, 25, Fig. 5) [65]. Most modifications again affected the B-pocket extensions, with many potent compounds showing a cyclohexyl-phenyl motif. However, the A pocket also seems to tolerate many changes, for example, the replacement of the phenyl ring by a cyclohexyl ring (25).

In two concurrent patent applications, Flexus described further modifications of the scaffold. In one, modifications to the B-pocket extension were mainly based on a cyclohexyl-quinoline motif, potentially with another substituent next to the amide (26, 27) [63]. In the other [64], modifications to the presumed heme-binding moieties are described, such as N-phenylamide to N-benzylamide, N-phenylsulfonamide, benzamide (28), phenylurea (29), aniline (30), and phenylacetamide (31, Fig. 5). The nanomolar activities of these compounds with electronically very different heme-facing moieties are quite astonishing and might suggest that the optimal filling of the B pocket plays a crucial role here.

In summary, the N-hydroxyamidine scaffold and related compounds have proven to provide a very promising route to the development of selective IDO1 inhibitors.

2.5 1,2,3-Triazoles

4-Aryl-1,2,3-triazoles were discovered in 2010, with the parent compound (32, Fig. 6) displaying an enzymatic IC50 value of 60 μM [44]. The rationally designed triazole 33 (MMG-0358) [110] showed nanomolar activities both in enzymatic and cellular assays, no cellular toxicity, and a high selectivity for IDO1 over TDO [110]. Nanomolar cellular IC50 values were also reported for the N-phenyl-1,2,3-triazol-4-amine compounds from Vertex (34) [74]. However, bioisosteric replacement of imidazole by 1,2,3-triazole in the NewLink Genetic fused compounds led to only moderatly active compounds (35) [112].
Fig. 6

Other IDO1 inhibitors with published activity data. 4-phenyl-1,2,3-triazole (32) [44, 110, 111], 1,2,3-triazoles (33, 34) [74, 110], fused 1,2-3-triazole (35) [112], benzenesulfonyl hydrazides (36, 37) [113, 114], triazolothiazole Amg-1 (38) [54], imidazothiazole (39) [42], aminonitrile (40) [59], iminonitrile (41) [61], and 2-amino-phenylureas (42, 43, 44) [55, 56, 115]

The 1,2,3-triazole scaffold provides an interesting alternative to the imidazole scaffold, as it could exhibit better specificity with respect to other heme proteins. However, no potent compounds with a B-pocket extension have been reported so far.

2.6 Phenyl Benzenesulfonylhydrazides

A series of phenyl benzenesulfonyl hydrazides (36, Fig. 6) displayed nanomolar IC50 values in both enzymatic and cellular assays [113]. In a further development of this scaffold, an optimized lead compound (37) with an enzymatic IC50 value of 36 nM, a cellular IC50 value of 68 nM, selectivity for IDO1 over 68 other protein targets, good oral bioavailability in rats, significant reduction of the Kyn/Trp ratio in the murine CT26 syngeneic colorectal cancer model, and significant tumor volume reduction in the same model was described [114].

2.7 Fused Thiazoles

The triazolo thiazole (Amg-1, 38, Fig. 6) was reported by Amgen to inhibit IDO1 with an enxymatic IC50 value of 3 μM, and its selectivity for IDO1 over IDO2 and TDO was demonstrated [54]. Amg-1 was later co-crystallized with IDO1 (Fig. 2b) and used for rational compound optimization. This led to the discovery of imidazothiazole derivatives occupying both pocket A and pocket B [42]. Nanomolar enzymatic inhibition activities were obtained with a urea linker, with the best compound in the series showing an enzymatic IC50 value of 77 nM (39).

2.8 Aminonitriles and Iminonitriles

Curadev reported aminonitriles as IDO1 inhibitors with enzymatic IC50 values below 200 nM [59]. One compound (40, Fig. 6) was shown to reduce plasma KYN levels by 40% in mice after inflammatory lipopolysaccharide (LPS) injection used to induce IDO1 expression. Later, the scaffold was modified to feature unsaturated iminonitriles and pyridines (41) [61]. For these compounds, only in vivo KYN level reduction values were given, which reached up to 87% after 2 h. Apparently, the predicted promiscuity of this scaffold due to their chemical reactivity as phenolic Mannich bases [75, 116, 117] does not hamper its in vivo use for IDO1 inhibition.

2.9 2-Amino-Phenylureas

In several patent applications, Bristol-Myers Squibb described a 2-amino-phenylurea scaffold and related compounds for IDO1 inhibition yielding low nanomolar to picomolar cellular IC50 values (42, 43, 44, Fig. 6) [55, 56, 57, 58, 115]. These are the most potent compounds reported to date, but no data is available about their specificity and mode of action. The three-dimensional structures of the compounds do not seem to be able to fill the IDO1 active site without clashing with surrounding protein residues, suggesting that they could display a novel alternative binding mode.

3 Tryptophan 2,3-Dioxygenase Inhibitors

TDO (EC 1.13.11.11), a functionally related but evolutionarily distant enzyme to IDO1, is constitutively expressed in the liver and regulates systemic L-Trp levels [16]. TDO is a tetrameric enzyme with a higher substrate specificity for L-Trp than IDO1. Recently, it was shown to play a complementary role in different types of cancer [25, 118]. There are nine X-ray structures of TDO available from the RCSB protein data bank, including a heme-free apo structure of human TDO [119] and a structure from xanthomonas campestris in complex with ferrous heme and tryptophan (Fig. 7) [120]. Xanthomonas campestris shares a 34% sequence identity with human TDO, and nine out of 11 L-Trp binding residues are conserved [120].
Fig. 7

X-ray structure of tryptophan 2,3-dioxygenase (TDO) (PDB ID 2NW8) from xanthomonas campestris in complex with ferrous heme and tryptophan [120]. Only the active site is shown, displaying the protein in surface representation, heme, selected protein side chains, and resolved solvent molecules in stick representation, and the ligand in ball and stick representation. Heteroatoms are colored as follows: blue (nitrogen), red (oxygen), and orange (iron). Hydrogen bonds are displayed as thin orange lines

3.1 6-Fluoro Indoles

L-Trp and its analogues 6-F-Trp and 5-F-Trp show a much higher affinity for TDO [120, 121] than IDO1, which facilitated the development of selective TDO inhibitors based on the indole scaffold (Fig. 8).
Fig. 8

TDO inhibitors based on 6-fluoro indole scaffold. 680C91 (45) [122, 123], 709W92 (46) [123, 124], LM10 (47) [25, 125], pyrazole derivatives (48, 49) [50], indazole derivative (50) [52], benzoxazole derivative (51) [52], pyridine derivatives (52, 53, 54) [51], and tetrahydropyridine derivative (55) [66]

The oldest and most used TDO inibitor is the 6-fluoroindole 680C91 (45) [122, 123], which displayed a Ki of 30 nM for rat TDO and was shown to be selective for TDO over IDO1 [122, 123]. Its regioisomer 709W92 (46) displayed the same Ki for rat TDO, but as it also inhibits serotonin uptake, it has been less used [123, 124]. Recently the Ki of 45 for human TDO was determined to be 880 nM (IC50 280 nM), but it was shown to suffer from limited solubility and bioavailability [25].

Based on these compounds and motivated by the discovery that TDO is implicated in tumoral immune escape, Frédérick and coworkers described a series of more than 70 derivatives of 45, systematically analyzing and varying all parts of the compound separately [125]. Cellular IC50 values on murine TDO were determined and used to develop a structure–activity relationship. Surprisingly, they did not find any compound more potent than 45, but replacing the pyridine ring by a negatively charged group such as a carboxylate or a tetrazole preserved the favorable interactions of L-Trp with Thr254 (Thr342 in hTDO) and Arg117 (Arg144 in hTDO, Fig. 7) and led to more soluble and stable compounds. In the selected lead compound (47), the pyridine ring was replaced by a tetrazole. This compound showed a Ki of 5.6 μM on a crude extract of human TDO as well as selectivity over hIDO1, type A and B monoamine oxidase, 15 receptors, and three transporters. Unlike the parent compound 45, it demonstrated a very good solubility and high oral bioavailability in mice [125]. Under the label LM10, 47 was used to show that TDO inhibition could reduce the growth of TDO-expressing P815 mastocytoma cells in mice without producing signs of liver toxicity [25].

Further work of iTeos Therapeutics on the indole scaffold led to the discovery of potent 3-substituted indole compounds with low micromolar or nanomolar enzymatic and cellular activities on hTDO (48, 49, 50, 51, 52, 53, 54). In three patents, they describe indoles with different heterocyclic substitutents. Besides citing nanomolar enzymatic and cellular activities, a few compounds were shown to increase circulating L-Trp in mice when administered orally by gavage at 100 mg/kg [50, 51, 52]. While pyrazole derivatives were less efficient in this respect (49, +40% L-Trp) [50], benzoxazole (51, +80% L-Trp) [52] and especially pyridines (54, +140% L-Trp) [51] were more efficient.

IOmet Pharma also developed 3-substituted indoles and oxindoles for IDO1 (Sect. 2.2) and TDO inhibition. Three compounds demonstrated nanomolar enzymatic IC50 values on TDO and selectivity over IDO1 [66]. The representative compound 55 was selective for TDO, with an anzymatic IC50 value of 6.3 μM (IDO1: >130 μM), and a cellular IC50 value of 250 nM (IDO1: >100 μM) [66, 126].

Most but not all of these indole-based TDO inhibitors contain a 6-fluoro substituent on the indole ring. For xanthomonas campestris TDO, it has been shown that 6-F-L-Trp has a high affinity for TDO and that it is an efficient TDO substrate [120].

3.2 Imidazoles

While selective IDO1-inhibiting imidazoles are described in Sect. 2.3, and dual IDO1/TDO compounds in Sect. 4.1, TDO-selective imidazole inhibitors have also been discovered (Fig. 9). In the very active imidazo-indole inhibitors developed by Redx Pharma (56, 57, 58, 59) [72], the hydroxylated alkyl chain of the imidazo-indole from NewLink Genetics (62, Fig. 10) was replaced by an ether or an amino linker. These compounds displayed at least about 20-fold selectivity for TDO over IDO1.
Fig. 9

Other TDO inhibitors. Fused imidazo-indoles (56, 57, 58, 59) [72], 4-substituted indazole (60) [70], and naphthotriazoledione (61) [127]. Stereocenters discussed in the main text are marked by an asterisk

Fig. 10

Dual IDO1/TDO inhibitors. Fused imidazole-indoles (62, 63, 64) [72, 112], fused imidazole-isoindoles (65, 66, 67) [73], 4-substituted indazoles (68, 69) [70], 3-aminoisoxazolopyridines (70, 71) [128], and furopyridines (72, 73, 74) [60]. Stereocenters discussed in the main text are marked by an asterisk

3.3 Indazoles

Replacing the indole scaffold by an indazole, IOmet Pharma developed selective TDO and dual IDO1/TDO inhibitors based on the indazol-4-amine scaffold [70]. Many compounds displayed at least 1.5 log units better enzymatic and cellular activities towards TDO than IDO1. Compound 60 is selective for TDO, with an enzymatic IC50 value of 85 nM vs. 12 μM.

3.4 Quinones

As early as 1961, it was shown that the quinones or hydroquinones catechol, quinol, p-quinone, L-dihydroxyphenylalanine, and L-epinephrine were able to inhibit TDO [129]. In 2014, a screening of 2,800 compounds from the library of the National Cancer Institute (USA) identified seven compounds inhibiting TDO, among them six quinones such as β-lapachone, taxifolin, nanaomycin A, and mitomycin C [130]. Later, the same group described derivatives of the naturally ocurring quinone isatin for TDO and IDO1 inhibition [131]. In these works, only enzymatic assay results were reported, and no additional tests were carried out.

Naphthotriazolediones were discovered as TDO inhibitors based on a structure-based virtual screening [127]. The best compound (61, Fig. 9) displayed an IC50 value of 30 nM on hTDO and 20-fold selectivity over IDO. Further investigations of this compound suggested that it does not act through redox cycling and that it is selective for TDO over several other unrelated targets.

4 Dual Indoleamine 2,3-Dioxygenase 1/Tryptophan 2,3-Dioxygenase Inhibitors

As both IDO1 and TDO seem to play complementary roles in cancers, and as their active sites share many similarities, development of dual IDO1/TDO inhibitors is particularly attractive (Fig. 10).

4.1 Imidazoles

After describing fused imidazo-isoindole derivatives for IDO1 inhibition (14, 15, Fig. 4), NewLink Genetics also described imidazo-indole derivatives to be dual potent inhibitors of IDO1 and TDO (62, 63, Fig. 10) [112].

Redx Pharma built upon the work of NewLink Genetics, describing nanomolar enzymatic IDO1 and TDO inhibitors based on both the imidazo-indole [72] and the imidazo-isoindole [73] scaffolds. They determined the enzymatic IC50 value of one of the four stereoisomers the imidazo-indole compound 62 to be 94 nM [72]. Some new imidazo-indoles, such as, for example, the ether (64), seemed to be nearly equipotent towards IDO1 and TDO. The imidazo-isoindoles described by Redx (65, 66, 67) [73] were somewhat more active towards TDO. Incorporation of a pyridine ring into the tricyclic scaffold was found to be beneficial (65, 67), and the placement of a second aromatic ring in the B pocket (67) was tolerated.

4.2 Indazoles

The indazol-4-amine scaffold developed by IOmet Pharma yielded selective TDO inhibitors (Sect. 3.3) and dual IDO1/TDI inhibitors [70]. Compounds 68, 69 displayed enzymatic IC50 values below 500 nM towards both IDO1 and TDO.

4.3 3-Aminoisoxazolopyridines

Researchers from the University of Auckland developed very small dual IDO1/TDO inhibitors based on the 3-aminoisoxazolopyridine scaffold (70, 71, Fig. 10) [128]. Compound 70 displayed an enzymatic IC50 value of 1–10 μM and a cellular IC50 value below 1 μM on IDO1, as well as a cellular IC50 value of 1–10 μM on TDO. It reduced the KYN/Trp ratio in plasma and tumors of a glioma mouse model, reduced tumor growth, and led to increased survival when administered in combination with an anti-PD1 antibody [128]. Compound 71 displayed even more potent enzymatic and cellular inhibition of IDO1 and TDO.

Bulky substituents on the pyridine ring as well as substituents of the amino group led to much less active compounds.

4.4 Furopyridines

Curadev reported di-amino substituted furopyridines as dual IDO1/TDO inhibitors (72, 73, 74, Fig. 10) [60]. Here, many compounds displayed enzymatic and cellular IC50 values below 200 nM on hIDO1 and enzymatic IC50 values below 500 nM on TDO. Two compounds, including compound 72, also inhibited IDO2 with nanomolar IC50 values. Reduction of LPS-induced plasma KYN levels in mice above 50% were reported for a number of compounds. Compounds 72 and 73 were shown to reduce tumor volumes in vivo in the murine CT26 syngeneic colorectal cancer model, to reduce KYN levels in tumor tissue, and to be capable of penetrating the blood–brain barrier [60].

5 Indoleamine 2,3-Dioxygenase 2 Inhibitors

According to recent work [16], human IDO2 is weakly expressed in the liver, testes, and thyroid, but in contrast to previous reports [86, 132] not in human tumors. Two commonly occurring single nucleotide polymorphisms in the coding region of human IDO2 lead to more than 25% of humans having enzymatically inactive IDO2 [27].

Only a few IDO2 inhibitors have been reported (Fig. 11), probably due to the difficulties in expressing and purifying active human IDO2 [133]. L-1MT (1, Fig. 3) has been reported to inhibit human IDO2 with Ki values in the range of 300 [85] to 425 μM [134]. In 2010, Incyte reported preliminary results of potent mouse IDO2 inhibitors with more than 100-fold selectivity over mIDO1 but did not disclose their structures [135].
Fig. 11

Indoleamine 2,3-dioxygenase 2 (IDO2) inhibitors. Tenatoprazole (75) [102], furopyridine (76) [60], 4-phenyl-1,2,3-triazole (77) [133], and tryptanthrine (78) [134]

Two years later, a library of 640 FDA-approved drugs were screened in cellular assays on mIDO1 and on mIDO2, and 12 compounds were reported to inhibit mIDO2 at low micromolar concentrations and with selectivity over mIDO1 [102]. For example, the proton pump inhibitor tenatoprazole (75) displayed cellular IC50 values of 1.8 and >100 μM for mIDO2 and mIDO1, respectively. However, these proton pump inhibitors are known to be prodrugs whose active sulfenamide moiety covalently binds with selected cysteine residues of hydrogen potassium ATPase [136]. Inhibition of IDO1 by cysteine-binding compounds such as ebselen has been demonstrated earlier [137]. Apparent lower inhibition of IDO1 could be due to the fact that the same incubation time was used for both enzymes, but as IDO1 degrades L-Trp much faster than IDO2 [133], this assay was not in its linear phase anymore.

Curadev reported two compounds (72, Fig. 10 and 76, Fig. 11) to inhibit both human IDO1 and human IDO2 in enzymatic assays with IC50 values below 1 μM [60].

4-phenyl-1,2,3-triazoles were tested for mIDO2 inhibition in cellular assays, and it was noted that compounds filling only the A pocket were highly selective for IDO1, while compounds filling both A and B pockets displayed similar cellular IC50 values for hIDO1 and mIDO2 in the micromolar range (77) [133].

Tryptanthrins were also reported as potent hIDO2 inhibitors, but they show much better inhibition of hIDO1 than of hIDO2 (78) [134].

In summary, it seems to be challenging to develop selective IDO2 inhibitors, and their practical value has not been unequivocally established.

6 Conclusions

Thus far, IDO1 and TDO inhibition has been the main approach to address L-Trp metabolism as therapeutic target. The regulation of their expression might have different effects, as IDO1 has been shown to act also as a signaling protein independently from its enzymatic function [138]. Therapeutic vaccination against IDO1 has demonstrated disease stabilization without toxicity in patients with non-small cell lung cancer (NSCLC) [139]. If tryptophan depletion is the main cause of immune suppression (tryptophan depletion hypothesis), interference with the sensing of low L-Trp levels by the stress kinase GCN2 and the mTOR signaling pathway may provide different access points. Therapeutic regulation of L-Trp levels by modulation of transcellular L-Trp transport might be an alternative [15]. On the other hand, if bioactive L-Trp metabolites such as L-kynurenine (KYN), 3-hydroxy-L-kynurenine (3-HK), kynurenic acid (KA), or quinolinic acid (QUIN) are mainly responsible for immune suppression (tryptophan utilization hypothesis) [8], the inhibition of downstream enzymes along the kynurenine pathway (Fig. 1) such as kynurenine monooxygenase (KMO) or kynurenine aminotransferase II (KAT II) [21] or the suppression of the signaling pathways of the kynurenines, for example, through the aryl hydrocarbon receptor (AhR) [118, 140, 141], could be additional viable targets. Here, knowledge gained from many years of research into neurological disorders may be of value [142].

Notes

Acknowledgements

We would like to thank Somi Reddy Majjigapu and Pierre Vogel for fruitful discussions. Financial support to U.R. and to V.Z. was provided by the Foundation Solidar-Immun (Lausanne, Switzerland). Molecular graphics were produced with the UCSF Chimera package [143]. Instant JChem 15.1.19.0, 2015, ChemAxon (http://www.chemaxon.com), was used for structure database management. MarvinSketch 15.1.19.0, 2015, ChemAxon (http://www.chemaxon.com) was used for drawing, displaying, and characterizing chemical structures.

References

  1. 1.
    Khalil DN, Smith EL, Brentjens RJ, Wolchok JD (2016) Nat Rev Clin Oncol 13:273. doi:10.1038/nrclinonc.2016.25CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Postow MA, Callahan MK, Wolchok JD (2015) J Clin Oncol 33:1974. doi:10.1200/JCO.2014.59.4358CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Jackson HJ, Rafiq S, Brentjens RJ (2016) Nat Rev Clin Oncol 13:370. doi:10.1038/nrclinonc.2016.36CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Yang JC, Rosenberg SA (2016) In: Tumor immunology, vol 130, 1st edn. Elsevier Inc., pp 279–294. doi: 10.1016/bs.ai.2015.12.006Google Scholar
  5. 5.
    Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP (2013) J Exp Med 210:1389. doi:10.1084/jem.20130066CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF, Immunother J (2014) Cancer 2:3. doi:10.1186/2051-1426-2-3CrossRefGoogle Scholar
  7. 7.
    Crunkhorn S (2014) Nat Rev Drug Discov 13:879. doi:10.1038/nrd4502CrossRefPubMedGoogle Scholar
  8. 8.
    Stone TW, Stoy N, Darlington LG (2013) Trends Pharmacol Sci 34:136. doi:10.1016/j.tips.2012.09.006CrossRefPubMedGoogle Scholar
  9. 9.
  10. 10.
    Munn DH, Mellor AL (2013) Trends Immunol 34:137. doi:10.1016/j.it.2012.10.001CrossRefPubMedGoogle Scholar
  11. 11.
    Barth H, Raghuraman S (2014) Crit Rev Microbiol 40:360. doi:10.3109/1040841X.2012.742037CrossRefPubMedGoogle Scholar
  12. 12.
    Wolf H (1974) Scand J Clin Lab Invest 33(suppl 136):1. doi:10.3109/00365517409104201CrossRefGoogle Scholar
  13. 13.
    Peters JC (1991) Adv Exp Med Biol 294:345. doi:10.1007/978-1-4684-5952-4_32CrossRefPubMedGoogle Scholar
  14. 14.
    Platten M, Wick W, Van den Eynde BJ (2012) Cancer Res 72:5435. doi:10.1158/0008-5472.CAN-12-0569CrossRefPubMedGoogle Scholar
  15. 15.
    Platten M, von Knebel Doeberitz N, Oezen I, Wick W, Ochs K (2015) Front Immunol 5:673. doi:10.3389/fimmu.2014.00673CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    van Baren N, Van den Eynde BJ (2015) Front Immunol 6:34. doi:10.3389/fimmu.2015.00034CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Badawy AAB, Namboodiri AMA, Moffett JR (2016) Clin Sci 130:1327. doi:10.1042/CS20160153CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL (1998) Science 281:1191CrossRefGoogle Scholar
  19. 19.
    Murakami Y, Ito H, Saito K (2015) In: Engin A, Engin BA (eds) Tryptophan metabolism: implications for biological processes, health and disease. Springer International Publishing, Cham, pp. 95–120Google Scholar
  20. 20.
    Vécsei L, Szalárdy L, Fülöp F, Toldi J (2013) Nat Rev Drug Discov 12:64. doi:10.1038/nrd3793CrossRefPubMedGoogle Scholar
  21. 21.
    Dounay AB, Tuttle JB, Verhoest PR (2015) J Med Chem 58:8762. doi:10.1021/acs.jmedchem.5b00461CrossRefPubMedGoogle Scholar
  22. 22.
    Yeung AW, Terentis AC, King NJ, Thomas SR (2015) Clin Sci 129:601. doi:10.1042/CS20140392CrossRefPubMedGoogle Scholar
  23. 23.
    Uyttenhove C, Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, Boon T, Van den Eynde BJ (2003) Nat Med 9:1269. doi:10.1038/nm934CrossRefPubMedGoogle Scholar
  24. 24.
    Opitz CA, Litzenburger UM, Opitz U, Sahm F, Ochs K, Lutz C, Wick W, Platten M (2011) PLoS One 6:e19823. doi:10.1371/journal.pone.0019823CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Pilotte L, Larrieu P, Stroobant V, Colau D, Dolušić E, Frédérick R, Plaen ED, Uyttenhove C, Wouters J, Masereel B, Van den Eynde BJ (2012) Proc Natl Acad Sci U S A 109:2497. doi:10.1073/pnas.1113873109CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ball HJ, Sanchez-Perez A, Weiser S, Austin CJD, Astelbauer F, Miu J, McQuillan JA, Stocker R, Jermiin LS, Hunt NH (2007) Gene 396:203. doi:10.1016/j.gene.2007.04.010CrossRefPubMedGoogle Scholar
  27. 27.
    Metz R, DuHadaway JB, Kamasani U, Laury-Kleintop L, Muller AJ, Prendergast GC (2007) Cancer Res 67:7082. doi:10.1158/0008-5472.CAN-07-1872CrossRefPubMedGoogle Scholar
  28. 28.
    Yuasa HJ, Hasegawa T, Nakamura T, Suzuki T (2007) Comp Biochem Physiol B Biochem Mol Biol 146:461. doi:10.1016/j.cbpb.2006.11.028CrossRefPubMedGoogle Scholar
  29. 29.
    van Baren N, Van den Eynde BJ (2015) Cancer Immunol Res 3:978. doi:10.1158/2326-6066.CIR-15-0095CrossRefPubMedGoogle Scholar
  30. 30.
    Murray PJ (2016) Nat Immunol 17:132. doi:10.1038/ni.3323CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Thomas S, DuHadaway J, Prendergast GC, Laury-Kleintop L (2014) J Cell Biochem 115:391. doi:10.1002/jcb.24674CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Van de Velde LA, Gingras S, Pelletier S, Murray PJ (2016) Cell Metab 23:389. doi:10.1016/j.cmet.2016.02.004CrossRefPubMedGoogle Scholar
  33. 33.
    Schmidt SK, Siepmann S, Kuhlmann K, Meyer HE, Metzger S, Pudelko S, Leineweber M, Däubener W (2012) PLoS One 7:e44797. doi:10.1371/journal.pone.0044797CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Prendergast GC, Smith C, Thomas S, Mandik-Nayak L, Laury-Kleintop L, Metz R, Muller AJ (2014) Cancer Immunol Immunother 63:721. doi:10.1007/s00262-014-1549-4CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Théate I, van Baren N, Pilotte L, Moulin P, Larrieu P, Renauld JC, Hervé C, Gutierrez-Roelens I, Marbaix E, Sempoux C, Van den Eynde BJ (2015) Cancer Immunol Res 3:161. doi:10.1158/2326-6066.CIR-14-0137CrossRefPubMedGoogle Scholar
  36. 36.
    Godin-Ethier J, Hanafi LA, Piccirillo CA, Lapointe R (2011) Clin Cancer Res 17:6985. doi:10.1158/1078-0432.CCR-11-1331CrossRefPubMedGoogle Scholar
  37. 37.
    Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC (2005) Nat Med 11:312. doi:10.1038/nm1196CrossRefPubMedGoogle Scholar
  38. 38.
    Liu X, Shin N, Koblish HK, Yang G, Wang Q, Wang K, Leffet L, Hansbury MJ, Thomas B, Rupar M, Waeltz P, Bowman KJ, Polam P, Sparks RB, Yue EW, Li Y, Wynn R, Fridman JS, Burn TC, Combs AP, Newton RC, Scherle PA (2010) Blood 115:3520. doi:10.1182/blood-2009-09-246124CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Yang S, Li X, Hu F, Li Y, Yang Y, Yan J, Kuang C, Yang Q (2013) J Med Chem 56:8321. doi:10.1021/jm401195nCrossRefPubMedGoogle Scholar
  40. 40.
    Li M, Bolduc AR, Hoda MN, Gamble DN, Dolisca SB, Bolduc AK, Hoang K, Ashley C, McCall D, Rojiani AM, Maria BL, Rixe O, MacDonald TJ, Heeger PS, Mellor AL, Munn DH, Johnson TS (2014) J Immunother Cancer 2:21. doi:10.1186/2051-1426-2-21CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Sugimoto H, Oda S, Otsuki T, Hino T, Yoshida T, Shiro Y (2006) Proc Natl Acad Sci U S A 103:2611. doi:10.1073/pnas.0508996103CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Tojo S, Kohno T, Tanaka T, Kamioka S, Ota Y, Ishii T, Kamimoto K, Asano S, Isobe Y (2014) ACS Med Chem Lett 5:1119. doi:10.1021/ml500247wCrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Peng YH, Ueng SH, Tseng CT, Hung MS, Song JS, Wu JS, Liao FY, Fan YS, Wu MH, Hsiao WC, Hsueh CC, Lin SY, Cheng CY, Tu CH, Lee LC, Cheng MF, Shia KS, Shih C, Wu S (2016) J Med Chem 59:282. doi:10.1021/acs.jmedchem.5b01390CrossRefPubMedGoogle Scholar
  44. 44.
    Röhrig UF, Awad L, Grosdidier A, Larrieu P, Stroobant V, Colau D, Cerundolo V, Simpson AJG, Vogel P, Van den Eynde BJ, Zoete V, Michielin O (2010) J Med Chem 53:1172. doi:10.1021/jm9014718CrossRefPubMedGoogle Scholar
  45. 45.
    Yue EW, Douty B, Wayland B, Bower M, Liu X, Leffet L, Wang Q, Bowman KJ, Hansbury MJ, Liu C, Wei M, Li Y, Wynn R, Burn TC, Koblish HK, Fridman JS, Metcalf B, Scherle PA, Combs AP (2009) J Med Chem 52:7364. doi:10.1021/jm900518fCrossRefPubMedGoogle Scholar
  46. 46.
    Koblish HK, Hansbury MJ, Bowman KJ, Yang G, Neilan CL, Haley PJ, Burn TC, Waeltz P, Sparks RB, Yue EW, Combs AP, Scherle PA, Vaddi K, Fridman JS (2010) Mol Cancer Ther 9:489. doi:10.1158/1535-7163.MCT-09-0628CrossRefGoogle Scholar
  47. 47.
    Tao M, Frietze W, Meloni DJ, Weng L, Zhou J, Pan Y (2015) Process for the synthesis of an indoleamine 2,3-dioxygenase inhibitor. Patent WO 2015/070007Google Scholar
  48. 48.
    Mautino MR, Jaipuri FA, Waldo J, Kumar S, Adams J, Van Allen C, Marcinowicz-Flick A, Munn D, Vahanian NN, Link CJ (2013) Proceedings of the 104th annual meeting of the American Association for Cancer Research. In: Cancer research, vol 73, Washington, DC, Philadelphia (PA)Google Scholar
  49. 49.
    Nayak A, Hao Z, Sadek R, Vahanian N, Ramsey W, Kennedy E, Mautino M, Link C, Bourbo P, Dobbins R, Adams K, Diamond A, Marshall L, Munn DH, Janik J, Khleif SN (2014) J Immunother Cancer 2:P250. doi:10.1186/2051-1426-2-S3-P250CrossRefPubMedCentralGoogle Scholar
  50. 50.
    Crosignani S, Cauwenberghs S, Deroose F, Driessens G (2015) 4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use. Patent WO 2015/067782Google Scholar
  51. 51.
    Crosignani S, Cauwenberghs S, Driessens G, Deroose F (2015) Novel 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use. Patent WO 2015/121812Google Scholar
  52. 52.
    Cauwenberghs S, Crosignani S, Driessens G, Deroose F (2015) Novel 3-indol substituted derivatives, pharmaceutical compositions and methods for use. Patent WO 2015/140717Google Scholar
  53. 53.
    Crosignani S, Cauwenberghs S, Driessens G, Deroose F (2015) Pyrrolidine-2,5-dione derivatives, pharmaceutical compositions and methods for use as IDO1 inhibitors. Patent WO 2015/173764Google Scholar
  54. 54.
    Meininger D, Zalameda L, Liu Y, Stepan LP, Borges L, McCarter JD, Sutherland CL (2011) Biochim Biophys Acta 1814:1947. doi:10.1016/j.bbapap.2011.07.023CrossRefPubMedGoogle Scholar
  55. 55.
    Balog J, Huang A, Chen B, Chen L, Shan W (2014) IDO inhibitors. Patent WO 2014/150646Google Scholar
  56. 56.
    Balog J, Huang A, Chen B, Chen L, Seitz S, Hart A, Markwalder J (2014) Inhibitors of indoleamine 2,3-dioxygenase (IDO). Patent WO 2014/150677Google Scholar
  57. 57.
    Markwalder J, Seitz S, Balog J, Huang A, Mandal S, Williams D, Hart A, Inghrim J (2015) IDO inhibitors. Patent WO 2015/002918Google Scholar
  58. 58.
    Markwalder J, Balog J, Huang A, Seitz S (2015) IDO inhibitors. Patent WO 2015/006520Google Scholar
  59. 59.
    Banerjee M, Middya S, Shrivastava R, Raina S, Surya A, Yadav VK, Kapoor KK (2014) Aminonitriles as kynurenine pathway inhibitors. Patent WO 2014/141110Google Scholar
  60. 60.
    Banerjee M, Middya S, Shrivastava R, Raina S, Surya A, Yadav DB, Yadav VK, Kapoor KK, Venkatesan A, Smith RA, Thompson SK (2014) Inhibitors of the kynurenine pathway. Patent WO 2014/186035Google Scholar
  61. 61.
    Middya S, Yadav DB, Shrivastava R, Raina S, Banerjee M, Surya A (2016) Novel iminonitrile derivatives. Patent WO 2016/027241Google Scholar
  62. 62.
    Jaen JC, Osipov M, Powers JP, Shunatona HP, Walker JR, Zibinsky M (2015) Immunoregulatory agents. Patent WO 2015/188085Google Scholar
  63. 63.
    Beck HP, Jaen JC, Osipov M, Powers JP, Reilly MK, Shunatona HP, Walker JR, Zibinsky M, Balog JA, Williams DK, Markwalder JA, Cherney EC, Shan W (2016) Immunoregulatory agents. Patent WO 2016/073770Google Scholar
  64. 64.
    Beck HP, Jaen JC, Osipov M, Powers JP, Reilly MK, Shunatona HP, Walker JR, Zibinsky M, Balog JA, Williams DK, Markwalder JA, Seitz SP, Cherney L, Zhang EC, Shan W (2016) Immunoregulatory agents. Patent WO 2016/073774Google Scholar
  65. 65.
    Beck HP, Jaen JC, Osipov M, Powers JP, Reilly MK, Shunatona HP, Walker JR, Zibinsky M, Balog JA, Williams DK, Guo W (2016) Immunoregulatory agents. Patent WO 2016/073738Google Scholar
  66. 66.
    Cowley P, Wise A (2015) Tryptophan-2,3-dioxygenase (TDO) and/or indolamine-2,3-dioxygenase (IDO) inhibitors and their use. Patent WO 2015/082499Google Scholar
  67. 67.
    Cowley P, Wise A (2015) Indole derivatives for use in medicine. Patent WO 2015/150097Google Scholar
  68. 68.
    Cowley P, Wise A (2016) Pharmaceutical compound. Patent WO 2016/026772Google Scholar
  69. 69.
    Cowley P, Wise A (2016) Inhibitors of tryptophan 2,3-dioxygenase or indoleamine 2,3-dioxygenase. Patent WO 2016/071283Google Scholar
  70. 70.
    Cowley P, Wise A (2016) Pharmaceutical compound. Patent WO 2016/071293Google Scholar
  71. 71.
    Sherer BA (2016) Cyclohexyl-ethyl substituted diaza- and triaza-tricyclic compounds as indole-amine-2,3-dioxygenase (IDO) antagonists for the treatment of cancer. Patent WO 2016/037026Google Scholar
  72. 72.
    Armer R, Bingham M, Pesnot T, Gignoux C (2016) 4h-imidazo[1,5-a]indole derivatives and their use as indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TD02) modulators. Patent WO 2016/051181Google Scholar
  73. 73.
    Armer R, Bingham M, Pesnot T, Gignoux C (2016) 6,7-heterocyclic fused 5h-pyrrolo[1,2-c]imidazole derivatives and their use as indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TD02) modulators. Patent WO 2016/059412Google Scholar
  74. 74.
    Boyall D, Davis C, Dodd J, Everitt S, Miller A, Weber P, Westcott J, Young S (2014) Compounds useful as inhibitors of indoleamine 2,3-dioxygenase. Patent WO 2014/081689Google Scholar
  75. 75.
    Röhrig UF, Majjigapu SR, Vogel P, Zoete V, Michielin O (2015) J Med Chem 58:9421. doi:10.1021/acs.jmedchem.5b00326CrossRefPubMedGoogle Scholar
  76. 76.
    Cady SG, Sono M (1991) Arch Biochem Biophys 291:326CrossRefGoogle Scholar
  77. 77.
    Peterson AC, Migawa MT, Martin MJ, Hamaker LK, Czerwinski KM, Zhang W, Arend RA, Fisette PL, Okazi Y, Will JA, Brown RR, Cook JM (1994) Med Chem Res 3:531Google Scholar
  78. 78.
    Hou DY, Muller AJ, Sharma MD, DuHadaway J, Banerjee T, Johnson M, Mellor AL, Prendergast GC, Munn DH (2007) Cancer Res 67:792. doi:10.1158/0008-5472.CAN-06-2925CrossRefPubMedGoogle Scholar
  79. 79.
    Nakashima H, Uto Y, Nakata E, Nagasawa H, Ikkyu K, Hiraoka N, Nakashima K, Sasaki Y, Sugimoto H, Shiro Y, Hashimoto T, Okamoto Y, Asakawa Y, Hori H (2008) Bioorg Med Chem 16:8661. doi:10.1016/j.bmc.2008.07.087CrossRefPubMedGoogle Scholar
  80. 80.
    Yu CJ, Zheng MF, Kuang CX, Huang WD, Yang Q (2010) J Alzheimers Dis 22:257. doi:10.3233/JAD-2010-100684CrossRefPubMedGoogle Scholar
  81. 81.
    Dolušić E, Larrieu P, Blanc S, Sapunaric F, Norberg B, Moineaux L, Colette D, Stroobant V, Pilotte L, Colau D, Ferain T, Fraser G, Galleni M, Frère JM, Masereel B, Van den Eynde B, Wouters J, Frédérick R (2011) Bioorg Med Chem 19:1550. doi:10.1016/j.bmc.2010.12.032CrossRefPubMedGoogle Scholar
  82. 82.
    Yuasa HJ, Ball HJ, Austin CJD, Hunt NH (2010) Comp Biochem Physiol B Biochem Mol Biol 157:10. doi:10.1016/j.cbpb.2010.04.006CrossRefPubMedGoogle Scholar
  83. 83.
    Austin CJD, Mailu BM, Maghzal GJ, Sanchez-Perez A, Rahlfs S, Zocher K, Yuasa HJ, Arthur JW, Becker K, Stocker R, Hunt NH, Ball HJ (2010) Amino Acids 39:565. doi:10.1007/s00726-010-0475-9CrossRefPubMedGoogle Scholar
  84. 84.
    Qian F, Liao J, Villella J, Edwards R, Kalinski P, Lele S, Shrikant P, Odunsi K (2012) Cancer Immunol Immunother 61:2013. doi:10.1007/s00262-012-1265-xCrossRefPubMedGoogle Scholar
  85. 85.
    Pantouris G, Serys M, Yuasa HJ, Ball HJ, Mowat CG (2014) Amino Acids 46:2155. doi:10.1007/s00726-014-1766-3CrossRefPubMedGoogle Scholar
  86. 86.
    Löb S, Königsrainer A, Zieker D, Brücher BLDM, Rammensee HG, Opelz G, Terness P (2009) Cancer Immunol Immunother 58:153. doi:10.1007/s00262-008-0513-6CrossRefPubMedGoogle Scholar
  87. 87.
    Löb S, Königsrainer A, Rammensee HG, Opelz G, Terness P (2009) Nat Rev Cancer 9:445. doi:10.1038/nrc2639CrossRefPubMedGoogle Scholar
  88. 88.
    Qian F, Villella J, Wallace PK, Mhawech-Fauceglia P, Tario JD, Andrews C, Matsuzaki J, Valmori D, Ayyoub M, Frederick PJ, Beck A, Liao J, Cheney R, Moysich K, Lele S, Shrikant P, Old LJ, Odunsi K (2009) Chem Rev 69:5498. doi:10.1158/0008-5472.CAN-08-2106CrossRefGoogle Scholar
  89. 89.
    Metz R, Rust S, DuHadaway JB, Mautino MR, Munn DH, Vahanian NN, Link CJ, Prendergast GC (2012) Oncoimmunology 1:1460. doi:10.4161/onci.21716CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Muller AJ, Malachowski WP, Prendergast GC (2005) Expert Opin Ther Targets 9:831. doi:10.1517/14728222.9.4.831CrossRefPubMedGoogle Scholar
  91. 91.
    Watanabe Y, Fujiwara M, Hayaishi O (1978) Biochem Biophys Res Commun 85:273. doi:10.1016/S0006-291X(78)80039-4CrossRefPubMedGoogle Scholar
  92. 92.
    Saito K, Chen CY, Masana M, Crowley JS, Markey SP, Heyes MP (1993) Biochem J 291:11. doi:10.1042/bj2910011CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Sono M, Roach M, Coulter E, Dawson J (1996) Chem Rev 96:2841. doi:10.1021/cr9500500CrossRefPubMedGoogle Scholar
  94. 94.
    Southan M, Truscott R, Jamie J, Pelosi L, Walker M, Maeda H, Iwamoto Y, Toné S (1996) Med Chem Res 6:343Google Scholar
  95. 95.
    Chauhan N, Basran J, Rafice SA, Efimov I, Millett ES, Mowat CG, Moody PCE, Handa S, Raven EL (2012) FEBS J 279:4501. doi:10.1111/febs.12036CrossRefPubMedGoogle Scholar
  96. 96.
    Dolušić E, Larrieu P, Blanc S, Sapunaric F, Pouyez J, Moineaux L, Colette D, Stroobant V, Pilotte L, Colau D, Ferain T, Fraser G, Galleni M, Frère JM, Masereel B, Van den Eynde B, Wouters J, Frédérick R (2011) Eur J Med Chem 46:3058. doi:10.1016/j.ejmech.2011.02.049CrossRefPubMedGoogle Scholar
  97. 97.
    Kondreddi RR, Jiricek J, Rao SPS, Lakshminarayana SB, Camacho LR, Rao R, Herve M, Bifani P, Ma NL, Kuhen K, Goh A, Chatterjee AK, Dick T, Diagana TT, Manjunatha UH, Smith PW (2013) J Med Chem 56:8849. doi:10.1021/jm4012774CrossRefPubMedGoogle Scholar
  98. 98.
    Stec J, Onajole OK, Lun S, Guo H, Merenbloom B, Vistoli G, Bishai WR, Kozikowski AP (2016) J Med Chem 59:6232–6247. doi:10.1021/acs.jmedchem.6b00415CrossRefPubMedGoogle Scholar
  99. 99.
    Schmidt SV, Schultze JL (2014) Front Immunol 5:384. doi:10.3389/fimmu.2014.00384CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Sono M, Cady SG (1989) Biochemistry 28:5392CrossRefGoogle Scholar
  101. 101.
    Kumar S, Jaller D, Patel B, LaLonde JM, DuHadaway JB, Malachowski WP, Prendergast GC, Muller AJ (2008) J Med Chem 51:4968. doi:10.1021/jm800512zCrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Bakmiwewa SM, Fatokun A, Tran A, Payne RJ, Hunt NH, Ball HJ (2012) Bioorg Med Chem Lett 22:7641. doi:10.1016/j.bmcl.2012.10.010CrossRefPubMedGoogle Scholar
  103. 103.
    Röhrig UF, Majjigapu SR, Chambon M, Bron S, Pilotte L, Colau D, Van den Eynde BJ, Turcatti G, Vogel P, Zoete V, Michielin O (2014) Eur J Med Chem 84:284. doi:10.1016/j.ejmech.2014.06.078CrossRefPubMedGoogle Scholar
  104. 104.
    Fallarini S, Massarotti A, Gesù A, Giovarruscio S, Coda Zabetta G, Bergo R, Giannelli B, Brunco A, Lombardi G, Sorba G, Pirali T (2016) Med Chem Commun 7:409. doi:10.1039/C5MD00317BCrossRefGoogle Scholar
  105. 105.
    Mautino M, Kumar S, Jaipuri F, Waldo J, Kesharwani T, Zhang X (2011) Imidazole derivatives as IDO inhibitors. Patent WO 2011/056652Google Scholar
  106. 106.
    Mautino M, Kumar S, Waldo J, Jaipuri F, Kesharwani T (2012) Fused imidazole derivatives useful as IDO inhibitors. Patent WO 2012/142237Google Scholar
  107. 107.
    Combs A, Yue E, Sparks R, Zhu W, Zhou J, Lin Q, Weng L, Yue T, Liu P (2010) 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase. Patent WO 2010/005958Google Scholar
  108. 108.
    Paul S, Roy A, Deka SJ, Panda S, Trivedi V, Manna D (2016) Eur J Med Chem 121:364. doi:10.1016/j.ejmech.2016.05.061CrossRefPubMedGoogle Scholar
  109. 109.
    Combs A, Zhu W, Sparks RB (2008) N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase. Patent WO 2008/058178Google Scholar
  110. 110.
    Röhrig UF, Majjigapu SR, Grosdidier A, Bron S, Stroobant V, Pilotte L, Colau D, Vogel P, Van den Eynde BJ, Zoete V, Michielin O (2012) J Med Chem 55:5270. doi:10.1021/jm300260vCrossRefPubMedGoogle Scholar
  111. 111.
    Huang Q, Zheng M, Yang S, Kuang C, Yu C, Yang Q (2011) Eur J Med Chem 46:5680. doi:10.1016/j.ejmech.2011.08.044CrossRefPubMedGoogle Scholar
  112. 112.
    Kumar S, Waldo J, Jaipuri F, Mautino M (2014) Tricyclic compounds as inhibitors of immunosuppression mediated by tryptophan metabolization. Patent WO 2014/159248Google Scholar
  113. 113.
    Cheng MF, Hung MS, Song JS, Lin SY, Liao FY, Wu MH, Hsiao W, Hsieh CL, Wu JS, Chao YS, Shih C, Wu SY, Ueng SH (2014) Bioorg Med Chem Lett 24:3403. doi:10.1016/j.bmcl.2014.05.084CrossRefPubMedGoogle Scholar
  114. 114.
    Lin SY, Yeh TK, Kuo CC, Song JS, Cheng MF, Liao FY, Chao MW, Huang HL, Chen YL, Yang CY, Wu MH, Hsieh CL, Hsiao W, Peng YH, Wu JS, Lin LM, Sun M, Chao YS, Shih C, Wu SY, Pan SL, Hung MS, Ueng SH (2016) J Med Chem 59:419. doi:10.1021/acs.jmedchem.5b01640CrossRefPubMedGoogle Scholar
  115. 115.
    Markwalder J, Seitz S, Balog J, Huang A, Williams DK, Chen L, Mandal SK (2015) IDO inhibitors. Patent WO 2015/031295Google Scholar
  116. 116.
    Baell JB, Holloway G (2010) J Med Chem 53:2719. doi:10.1021/jm901137jCrossRefGoogle Scholar
  117. 117.
    Bruns RF, Watson I (2012) J Med Chem 55:9763. doi:10.1021/jm301008nCrossRefPubMedGoogle Scholar
  118. 118.
    Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M (2011) Nature 478:197. doi:10.1038/nature10491CrossRefPubMedGoogle Scholar
  119. 119.
    Meng B, Wu D, Gu J, Ouyang S, Ding W, Liu ZJ (2014) Proteins 82:3210. doi:10.1002/prot.24653CrossRefPubMedGoogle Scholar
  120. 120.
    Forouhar F, Anderson JLR, Mowat CG, Vorobiev SM, Hussain A, Abashidze M, Bruckmann C, Thackray SJ, Seetharaman J, Tucker T, Xiao R, Ma LC, Zhao L, Acton TB, Montelione GT, Chapman SK, Tong L (2007) Proc Natl Acad Sci U S A 104:473. doi:10.1073/pnas.0610007104CrossRefPubMedGoogle Scholar
  121. 121.
    Thackray SJ, Bruckmann C, Anderson JLR, Campbell LP, Xiao R, Zhao L, Mowat CG, Forouhar F, Tong L, Chapman SK (2008) Biochemistry 47:10677. doi:10.1021/bi801202aCrossRefPubMedGoogle Scholar
  122. 122.
    Salter M, Hazelwood R, Pogson CI, Iyer R, Madge DJ (1995) Biochem Pharmacol 49:1435CrossRefGoogle Scholar
  123. 123.
    Madge D, Hazelwood R, Iyer R, Jones H, Salter M (1996) Bioorg Med Chem Lett 6:857. doi:10.1016/0960-894X(96)00124-2CrossRefGoogle Scholar
  124. 124.
    Salter M, Hazelwood R, Pogson CI, Iyer R, Madge DJ, Jones HT, Cooper BR, Cox RF, Wang CM, Wiard RP (1995) Neuropharmacology 34:217CrossRefGoogle Scholar
  125. 125.
    Dolušić E, Larrieu P, Moineaux L, Stroobant V, Pilotte L, Colau D, Pochet L, Van den Eynde B, Masereel B, Wouters J, Frédérick R (2011) J Med Chem 54:5320. doi:10.1021/jm2006782CrossRefPubMedGoogle Scholar
  126. 126.
    Hunter B, McElroy S, Wise A (2015) Screening method. Patent WO 2015/091862Google Scholar
  127. 127.
    Wu JS, Lin SY, Liao FY, Hsiao WC, Lee LC, Peng YH, Hsieh CL, Wu MH, Song JS, Yueh A, Chen CH, Yeh SH, Liu CY, Lin SY, Yeh TK, Hsu JTA, Shih C, Ueng SH, Hung MS, Wu SY (2015) J Med Chem 58:7807. doi:10.1021/acs.jmedchem.5b00921CrossRefPubMedGoogle Scholar
  128. 128.
    Palmer BD, Ching LM, Gamage SA (2015) Inhibitors of tryptophan dioxygenases (IDO1 and TDO) and their use in therapy. Patent WO 2015/024233Google Scholar
  129. 129.
    Frieden E, Westmark GW, Schor JM (1961) Arch Biochem Biophys 92:176CrossRefGoogle Scholar
  130. 130.
    Pantouris G, Mowat CG (2014) Biochem Biophys Res Commun 443:28. doi:10.1016/j.bbrc.2013.11.037CrossRefPubMedGoogle Scholar
  131. 131.
    Pantouris G, Loudon-Griffiths J, Mowat CG (2016) J Enzyme Inhib Med Chem 6366:1. doi:10.3109/14756366.2016.1170013CrossRefGoogle Scholar
  132. 132.
    Witkiewicz AK, Costantino CL, Metz R, Muller AJ, Prendergast GC, Yeo CJ, Brody JR (2009) J Am Coll Surg 208:781. doi:10.1016/j.jamcollsurg.2008.12.018CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Röhrig UF, Majjigapu SR, Caldelari D, Dilek N, Reichenbach P, Ascencao K, Irving M, Coukos G, Vogel P, Zoete V, Michielin O (2016) Bioorg Med Chem Lett 26:4330. doi:10.1016/j.bmcl.2016.07.031CrossRefPubMedGoogle Scholar
  134. 134.
    Li J, Li Y, Yang D, Hu N, Guo Z, Kuang C, Yang Q (2016) Eur J Med Chem 123:171. doi:10.1016/j.ejmech.2016.07.013CrossRefPubMedGoogle Scholar
  135. 135.
    Liu X, Yang G, Wang Q, Leffet L, Katiyar K, Waeltz P, Burns T, Combs A, Newton R, Scherle P (2010) EJC Suppl 8:206. doi:10.1016/S1359-6349(10)72367-3CrossRefGoogle Scholar
  136. 136.
    Welage LS (2003) Pharmacotherapy 23:74S. doi:10.1592/phco.23.13.74S.31929CrossRefPubMedGoogle Scholar
  137. 137.
    Terentis AC, Freewan M, Sempértegui Plaza TS, Raftery MJ, Stocker R, Thomas SR (2010) Biochemistry 49:591. doi:10.1021/bi901546eCrossRefPubMedGoogle Scholar
  138. 138.
    Pallotta MT, Orabona C, Volpi C, Vacca C, Belladonna ML, Bianchi R, Servillo G, Brunacci C, Calvitti M, Bicciato S, Mazza EMC, Boon L, Grassi F, Fioretti MC, Fallarino F, Puccetti P, Grohmann U (2011) Nat Immunol 12:870. doi:10.1038/ni.2077CrossRefPubMedGoogle Scholar
  139. 139.
    Andersen MH, Svane IM (2015) Oncoimmunology 4:e983770. doi:10.4161/2162402X.2014.983770CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA (2010) J Immunnol 185:3190. doi:10.4049/jimmunol.0903670CrossRefGoogle Scholar
  141. 141.
    Bessede A, Gargaro M, Pallotta MT, Matino D, Servillo G, Brunacci C, Bicciato S, Mazza EMC, Macchiarulo A, Vacca C, Iannitti R, Tissi L, Volpi C, Belladonna ML, Orabona C, Bianchi R, Lanz TV, Platten M, Della Fazia MA, Piobbico D, Zelante T, Funakoshi H, Nakamura T, Gilot D, Denison MS, Guillemin GJ, DuHadaway JB, Prendergast GC, Metz R, Geffard M, Boon L, Pirro M, Iorio A, Veyret B, Romani L, Grohmann U, Fallarino F, Puccetti P (2014) Nature 511:184. doi:10.1038/nature13323CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Maddison DC, Giorgini F (2015) Semin Cell Dev Biol 40:134. doi:10.1016/j.semcdb.2015.03.002CrossRefPubMedGoogle Scholar
  143. 143.
    Pettersen EF, Goddard T, Huang C, Couch G, Greenblatt D, Meng E, Ferrin TE (2004) J Comput Chem 25:1605CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.SIB Swiss Institute of BioinformaticsLausanneSwitzerland
  2. 2.Ludwig Center for Cancer Research of the University of Lausanne, Dep. of OncologyUniv. of Lausanne and Centre Hospitalier Universitaire Vaudois (CHUV)LausanneSwitzerland

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