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Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond

Abstract

l-Tryptophan (Trp) metabolism through the kynurenine pathway (KP) is involved in the regulation of immunity, neuronal function and intestinal homeostasis. Imbalances in Trp metabolism in disorders ranging from cancer to neurodegenerative disease have stimulated interest in therapeutically targeting the KP, particularly the main rate-limiting enzymes indoleamine-2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan-2,3-dioxygenase (TDO) as well as kynurenine monooxygenase (KMO). However, although small-molecule IDO1 inhibitors showed promise in early-stage cancer immunotherapy clinical trials, a phase III trial was negative. This Review summarizes the physiological and pathophysiological roles of Trp metabolism, highlighting the vast opportunities and challenges for drug development in multiple diseases.

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Fig. 1: Tryptophan catabolism, key therapeutic targets and drugs in development.
Fig. 2: Tryptophan catabolism — key organs involved.
Fig. 3: Neuroactivity of tryptophan metabolites.
Fig. 4: Immunological effects of tryptophan metabolism.
Fig. 5: Different binding mechanisms of IDO1 inhibitors.

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Acknowledgements

This work was supported by grants from the German Cancer Aid (70110392) and German Research Foundation (DFG PL-315/5-1) to M.P.; the Italian Association of Cancer Research (19903) and Telethon (GGP17094) to F.F.; the German Federal Ministry of Education and Research (BMBF) e:Med initiative (GlioPATH, 01ZX1402), the European Research Council (ERC) and the alumni chapter of Gooische Groningers facilitated by Ubbo Emmius Fonds to E.A.A.N; and funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 754688 to C.A.O. The authors thank F. Sorgdrager for Fig. 2 and A. Sadik for help with Table 2.

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Correspondence to Michael Platten.

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M.P. has received royalties for patents on aryl hydrocarbon receptor inhibitors and tryptophan metabolites and has received honoraria for advisory board services and research support from Bayer. E.A.A.N., F.F., U.F.R. and C.A.O. declare no competing interests.

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Glossary

Kynurenine (Kyn) pathway

(KP). The major pathway in the metabolism of the essential amino acid tryptophan, which contains many immunoactive and neuroactive intermediate metabolites.

Indoleamine-2,3-dioxygenase 1

(IDO1). The first enzyme discovered to initiate immunosuppressive kynurenine pathway metabolism. IDO1 and tryptophan-2,3-dioxygenase (TDO) represent a key intracellular immune checkpoint.

Kynurenine aminotransferases

(KATI–KATIII). KATs catalyse the conversion of kynurenine to kynurenic acid (KA) and of 3-hydroxykynurenine to KA and are a drug target for schizophrenia and cognitive impairment disorders.

Kynurenine monooxygenase

(KMO). A key kynurenine pathway (KP) enzyme and drug target that controls the conversion of kynurenine to neuroactive and immunoregulatory KP metabolites.

Quinolinic acid

(QA). A key kynurenine pathway metabolite accumulating in the brain during inflammation and mediating neuronal death through the activation of N-methyl-d-aspartate (NMDA) receptors, a process termed excitotoxicity.

NAD+

A key coenzyme in metabolic processes and redox reactions regulating cellular fitness, for which the kynurenine pathway is a major source.

Immune checkpoint inhibitors

Antibodies for cancer immunotherapy, which act by neutralizing inhibitory pathways in T cells, thereby enhancing antitumor immunity.

General control non-derepressible 2

(GCN2). A kinase leading to dysfunction of T cells and antigen-presenting cells in response to extreme l-tryptophan shortage (<1 µM).

Aryl hydrocarbon receptor

(AHR). A cytosolic transcription factor originally described as a mediator of xenobiotic detoxification but increasingly shown to mediate important functions of tryptophan metabolism by binding kynurenine and kynurenic acid.

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Platten, M., Nollen, E.A.A., Röhrig, U.F. et al. Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat Rev Drug Discov 18, 379–401 (2019). https://doi.org/10.1038/s41573-019-0016-5

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