Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond.
Michael PlattenEllen A A NollenUte F RöhrigFrancesca FallarinoChristiane A OpitzPublished in: Nature reviews. Drug discovery (2019)
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.
Keyphrases
- phase iii
- clinical trial
- small molecule
- early stage
- papillary thyroid
- phase ii
- open label
- squamous cell
- double blind
- study protocol
- squamous cell carcinoma
- randomized controlled trial
- young adults
- lymph node metastasis
- cancer therapy
- lymph node
- big data
- neoadjuvant chemotherapy
- blood brain barrier
- artificial intelligence