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

Michael Platten; Ellen A A Nollen; Ute F Röhrig; Francesca Fallarino; Christiane A Opitz

doi:10.1038/s41573-019-0016-5

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

Michael Platten, Ellen A A Nollen, Ute F Röhrig, Francesca Fallarino, Christiane A Opitz

Research output: Contribution to journal › Review article › peer-review

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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.

Original language	English
Pages (from-to)	379-401
Number of pages	23
Journal	Nature Reviews Drug Discovery
Volume	18
Issue number	8
DOIs	https://doi.org/10.1038/s41573-019-0016-5
Publication status	Published - May-2019

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Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyondFinal publisher's version, 2.96 MBLicence: Taverne

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title = "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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T1 - Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond

AU - Platten, Michael

AU - Nollen, Ellen A A

AU - Röhrig, Ute F

AU - Fallarino, Francesca

AU - Opitz, Christiane A

PY - 2019/5

Y1 - 2019/5

N2 - 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.

AB - 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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DO - 10.1038/s41573-019-0016-5

M3 - Review article

C2 - 30760888

SN - 1474-1776

VL - 18

SP - 379

EP - 401

JO - Nature Reviews Drug Discovery

JF - Nature Reviews Drug Discovery

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ER -

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

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