Recent advances in clinical trials targeting the kynurenine pathway

Ananda Staats Pires, Gayathri Sundaram, Benjamin Heng*, Shivani Krishnamurthy, Bruce J. Brew, Gilles J. Guillemin

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

Abstract

The kynurenine pathway (KP) is the major catabolic pathway for the essential amino acid tryptophan leading to he production of nicotinamide adenine dinucleotide. In inflammatory conditions, the activation of the KP leads to the production of several bioactive metabolites including kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, kynurenic acid and quinolinic acid. These metabolites can have redox and immune suppressive activity, be neurotoxic or neuroprotective. While the activity of the pathway is tightly regulated under normal physiological condition, it can be upregulated by immunological activation and inflammation. The dysregulation of the KP has been implicated in wide range of neurological diseases and psychiatric disorders. In this review, we discuss the mechanisms involved in KP-mediated neurotoxicity and immune suppression, and its role in diseases of our expertise including cancer, chronic pain and multiple sclerosis. We also provide updates on the clinical trials evaluating the efficacy of KP inhibitors and/or analogues in each respective disease.

Original languageEnglish
Article number108055
Pages (from-to)1-32
Number of pages32
JournalPharmacology and Therapeutics
Volume236
Early online date17 Dec 2021
DOIs
Publication statusE-pub ahead of print - 17 Dec 2021

Keywords

  • Chronic pain
  • Immune evasion
  • Indoleamine 2,3 dioxygenase 1
  • Kynurenine pathway
  • Multiple sclerosis
  • Neuroinflammation
  • Neuropathic pain
  • quinolinic acid

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