Tryptophan 2,3-Dioxygenase (TDO) Inhibitors. 3-(2-(Pyridyl)ethenyl)indoles as Potential Anticancer Immunomodulators

Dolušić, Eduard; Larrieu, Pierre; Moineaux, Laurence; Stroobant, Vincent; Pilotte, Luc; Colau, Didier; Pochet, Lionel; Eynde, Benoı̂t Van den; Masereel, Bernard; Wouters, Johan; Frédérick, Raphaël

doi:10.1021/jm2006782

Cited by 153 publications

(74 citation statements)

References 52 publications

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“…A recent report published during the reviewing process of this paper corroborates our findings by showing that TDO is expressed constitutively in human glioblastomas and promotes tumor progression through the production of kynurenine acting as endogenous ligand of the aryl hydrocarbon receptor, resulting in increased tumor cell survival and motility, and reduced antitumor immune responses (36). In our tumor model, however, we did not observe a tumor cell autonomous effect of TDO activity, (16). A cellular assay based on mouse P815B-mTDO, mouse P815B-mIDO, or human 293E-hTDO cells was used to measure IC50, defined as the concentration giving 50% inhibition of TDO activity at a L-tryptophan concentration of 80 μM.…”

Section: Discussionsupporting

confidence: 90%

“…2A). We thus started a medicinal chemistry program aimed at improving the aqueous solubility and bioavailability in this series (16). This eventually led to the discovery of compound LM10, which is characterized by a 6-fluoro-indole substituted in the 3-position by a tetrazolyl-vinyl side chain and displays a good TDO inhibition (Ki = 5.6 μM) with a competitive inhibition profile ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Solubility was evaluated at room temperature as described in ref. 16. Bioavailability was estimated by measuring plasma concentration of the compounds after 1, 2, or 7 d of oral administration of 160 mg/kg/day.…”

Section: Discussionmentioning

confidence: 99%

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

Pilotte

Larrieu

Stroobant

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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496

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Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO1) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance, and IDO1 inhibition is an active area of drug development. Tryptophan 2,3-dioxygenase (TDO) is an unrelated hepatic enzyme that also degrades tryptophan along the kynurenine pathway. Here, we show that enzymatically active TDO is expressed in a significant proportion of human tumors. In a preclinical model, TDO expression by tumors prevented their rejection by immunized mice. We developed a TDO inhibitor, which, upon systemic treatment, restored the ability of mice to reject TDO-expressing tumors. Our results describe a mechanism of tumoral immune resistance based on TDO expression and establish proof-of-concept for the use of TDO inhibitors in cancer therapy.T ryptophan 2,3-dioxygenase (TDO) is a homotetrameric hemecontaining cytosolic enzyme encoded by gene TDO2 and expressed at high levels in the liver. It catalyses the first and ratelimiting step of tryptophan degradation along the kynurenine pathway and thereby regulates systemic tryptophan levels. The same reaction can be catalyzed by another heme-containing cytosolic enzyme, named indoleamine 2,3-dioxygenase (IDO1), which has no sequence similarity with TDO, is not expressed in the liver, and is monomeric. IDO1 has been the focus of attention in recent years because of its immunosuppressive effects on T lymphocytes, resulting partly from tryptophan depletion and partly from direct effects of tryptophan catabolites (1-3). IDO1 is expressed constitutively in the placenta, where it plays a key role in feto-maternal tolerance (2), and in many tumors, where it contributes to tumoral resistance to immune rejection (4-7). IDO1 expression is also inducible in many cells, including dendritic cells, and appears to play a role in peripheral immune tolerance and the retro-control of immune responses (8). In contrast, little is known about the effect of TDO expression on the immune response. A recent report indicated that human cells transfected with TDO depleted tryptophan and thereby prevented both the growth of pathogens and the proliferation of allogeneic T lymphocytes (9). These results suggested that TDO might mediate immunosuppressive effects similar to those of IDO1. We set out to examine whether tumor cells express TDO and thereby inhibit T-cell-mediated immune responses. ResultsWe first observed that many human tumor samples expressed gene TDO2 as measured by real-time RT-PCR (Table 1). This was the case for 41% of bladder carcinomas, 50% of melanomas and 100% of hepatocarcinomas. To confirm the activity of TDO in tumor cells, we selected a series of human tumor cell lines that also expressed the TDO2 mRNA. We incubated cells for 24 h in medium containing a known concentration of tryptophan, and measured by HPLC in the supernatant the concentration of tryptophan and kynurenine, which is the main tryptophan catabolite (Table 2). HEK-293 cells transfected or not with human TDO2 were used as pos...

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Section: Discussionsupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

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

Pilotte

Larrieu

Stroobant

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

496

532

View full text Add to dashboard Cite

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“…In IDO-negative glioma cells, TDO seems to be the sole determinant of constitutive Trp degradation, indicating that TDO represents a novel therapeutic target in glioma therapy. In fact, an orally available TDO inhibitor has recently been developed 16 . Inhibition of TDO may not only restore antitumour immune responses but also act on the tumour cell intrinsic malignant phenotype, because we delineated the importance of constitutive Trp degradation to sustain the malignant phenotype of cancer by acting on the tumour cells themselves.…”

Section: Discussionmentioning

confidence: 99%

An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor

Opitz

Litzenburger

Sahm

et al. 2011

Nature

1,532

1,534

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“…Indeed, the AhR antagonist a-NF (a pseudoligand that binds to the Ah receptor to form a nonfunctional complex) exhibits single-agent efficacy in inhibiting cell-cycle progression (42) and inducing apoptosis in cancer cells expressing high level of endogenous AhR (as shown in this study). In addition, the indoleamine 2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) inhibitors that inhibit Kyn, an endogenous AhR ligand, potentiate chemotherapy and immunotherapy, and clinical trials evaluating their safety and efficacy in cancers are currently underway (43)(44)(45). Interestingly, the AhR high cells tend to have a much higher magnitude of Kyn synthase expression than the AhR low cells ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Aryl Hydrocarbon Receptor Leads to Resistance to EGFR TKIs in Non–Small Cell Lung Cancer by Activating Src-mediated Bypass Signaling

Zhang

Gao

et al. 2018

Clinical Cancer Research

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Purpose: The aryl hydrocarbon receptor (AhR) has been generally recognized as a ligand-activated transcriptional factor that responds to xenobiotic chemicals. Recent studies have suggested that the expression of AhR varies widely across different cancer types and cancer cell lines, but its significance in cancer treatment has yet to be clarified. Experimental Design: AhR expression in non–small cell lung cancer (NSCLC) was determined by Western blotting and IHC staining. In vitro and in vivo functional experiments were performed to determine the effect of AhR on sensitivity to targeted therapeutics. A panel of biochemical assays was used to elucidate the underlying mechanisms. Results: A high AhR protein level indicated an unfavorable prognosis for lung adenocarcinoma. Inhibition of AhR signaling sensitized EGFR tyrosine kinase inhibitors (TKIs) in NSCLC cells that express high level of endogenous AhR protein. Notably, activation of AhR by pharmacologic and molecular approaches rendered EGFR-mutant cells resistant to TKIs by restoring PI3K/Akt and MEK/Erk signaling through activation of Src. In addition, we found that AhR acts as a protein adaptor to mediate Jak2–Src interaction, which does not require the canonical transcriptional activity of AhR. Conclusions: Our results reveal a transcription-independent function of AhR and indicate that AhR may act as a protein adaptor that recruits kinases bypassing EGFR and drives resistance to TKIs. Accordingly, targeting Src would be a strategy to overcome resistance to EGFR TKIs in AhR-activated NSCLC. Clin Cancer Res; 24(5); 1227–39. ©2017 AACR.

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Tryptophan 2,3-Dioxygenase (TDO) Inhibitors. 3-(2-(Pyridyl)ethenyl)indoles as Potential Anticancer Immunomodulators

Cited by 153 publications

References 52 publications

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

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

An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor

Activation of the Aryl Hydrocarbon Receptor Leads to Resistance to EGFR TKIs in Non–Small Cell Lung Cancer by Activating Src-mediated Bypass Signaling

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