Inhibitors of the Kynurenine Pathway
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.
KeywordsImmuno-oncology Indoleamine 2,3-dioxygenase Kynurenine pathway Tryptophan 2,3-dioxygenase Tryptophan metabolism
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 188.8.131.52) is the most well-established target in the kynurenine pathway for cancer immunotherapy . 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 . 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].
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 , Bristol-Myers Squibb [55, 56, 57, 58], Curadev [59, 60, 61] (partnering with Roche), Dainippon Sumitomo Pharma Corporation , 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 , Redx Pharma [72, 73], and Vertex Pharmaceuticals  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 . 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 . 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.
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.
IDO1 inhibitors known before the implication of this enzyme in tumoral immune resistance were of moderate micromolar activity . 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) . 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 .
In the following, IOmet Pharma described a large series of indole-2-carboxamides . 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 .
More recently, iTeos Therapeutics described a series of 3-indol-3-yl-pyrrolidine-2,5-diones (succinimides) with potent IDO1 inhibitory properties . 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.
Fallarini and coworkers created a virtual library of 1,5- and 4,5-disubstituted imidazoles and selected 25 compounds for synthesis and evaluation . 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) . 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 . 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 . 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 .
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) . The most potent compound described in this work, which corresponds to compound 15 (Fig. 4) , 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 . 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 . 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) , 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
Nitrobenzofurazan derivatives of the N-hydroxyamidine scaffold (20)  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) . 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) . 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) . In the other , 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.
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 . 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 .
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 . 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 . 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 . 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) . 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.
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
3.1 6-Fluoro Indoles
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 .
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 . 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 . 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 .
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) , benzoxazole (51, +80% L-Trp)  and especially pyridines (54, +140% L-Trp)  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 . 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 .
Replacing the indole scaffold by an indazole, IOmet Pharma developed selective TDO and dual IDO1/TDO inhibitors based on the indazol-4-amine scaffold . 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.
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 . 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 . Later, the same group described derivatives of the naturally ocurring quinone isatin for TDO and IDO1 inhibition . 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 . 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).
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) .
Redx Pharma built upon the work of NewLink Genetics, describing nanomolar enzymatic IDO1 and TDO inhibitors based on both the imidazo-indole  and the imidazo-isoindole  scaffolds. They determined the enzymatic IC50 value of one of the four stereoisomers the imidazo-indole compound 62 to be 94 nM . 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)  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.
The indazol-4-amine scaffold developed by IOmet Pharma yielded selective TDO inhibitors (Sect. 3.3) and dual IDO1/TDI inhibitors . Compounds 68, 69 displayed enzymatic IC50 values below 500 nM towards both IDO1 and TDO.
Researchers from the University of Auckland developed very small dual IDO1/TDO inhibitors based on the 3-aminoisoxazolopyridine scaffold (70, 71, Fig. 10) . 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 . 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.
Curadev reported di-amino substituted furopyridines as dual IDO1/TDO inhibitors (72, 73, 74, Fig. 10) . 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 .
5 Indoleamine 2,3-Dioxygenase 2 Inhibitors
According to recent work , 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 .
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 . 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 . Inhibition of IDO1 by cysteine-binding compounds such as ebselen has been demonstrated earlier . 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 , this assay was not in its linear phase anymore.
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) .
Tryptanthrins were also reported as potent hIDO2 inhibitors, but they show much better inhibition of hIDO1 than of hIDO2 (78) .
In summary, it seems to be challenging to develop selective IDO2 inhibitors, and their practical value has not been unequivocally established.
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 . Therapeutic vaccination against IDO1 has demonstrated disease stabilization without toxicity in patients with non-small cell lung cancer (NSCLC) . 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 . 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) , the inhibition of downstream enzymes along the kynurenine pathway (Fig. 1) such as kynurenine monooxygenase (KMO) or kynurenine aminotransferase II (KAT II)  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 .
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 . Instant JChem 184.108.40.206, 2015, ChemAxon (http://www.chemaxon.com), was used for structure database management. MarvinSketch 220.127.116.11, 2015, ChemAxon (http://www.chemaxon.com) was used for drawing, displaying, and characterizing chemical structures.
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