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Nat Rev Drug Discov. 2019 May;18(5):379-401. doi: 10.1038/s41573-019-0016-5.

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

Author information

1
DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany. m.platten@Dkfz-Heidelberg.de.
2
Department of Neurology, University of Heidelberg, Medical Faculty Mannheim, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany. m.platten@Dkfz-Heidelberg.de.
3
University of Groningen, European Research Institute for the Biology of Ageing, University Medical Center Groningen, Antonius Deusinglaan 1, Groningen, Netherlands.
4
Molecular Modelling Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
5
Department of Experimental Medicine, University of Perugia, Perugia, Italy.
6
DKTK Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany.
7
Neurology Clinic and National Center for Tumor Diseases, University Hospital of Heidelberg, INF 400, Heidelberg, Germany.

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.

PMID:
30760888
DOI:
10.1038/s41573-019-0016-5

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