New promises for manipulation of kynurenine pathway in cancer and neurological diseases

Abstract

Background: The kynurenine pathway (KP), the primary route of tryptophan degradation in mammalian cells, consists of a cascade of enzymatic reactions eventually leading to NAD⁺ formation. Many metabolites along the route have biological activities, especially in the nervous and immune systems. Objective/methods: This review focuses on three therapeutic areas, tumor immunoediting, schizophrenia, and Huntington's disease, apparently disconnected but linked by preliminary proof-of-concept of KP involvement. The potential embedded in drug discovery programs aimed at the identification of selective inhibitors with optimized pharmacodynamic and pharmacokinetic properties for human studies is discussed. Results/conclusions: Recent advances have shifted the attention on the kynurenine pathway from a scientific curiosity to a clinically relevant collection of targets. A relatively large number of ligands able to interfere with individual enzymes of the pathway have been made available, but none have so far proceeded into advanced clinical studies.

Keywords::

• 3HAD
• Huntington's disease
• IDO
• immunoediting
• KAT
• kynurenine pathway
• kynurenines
• schizophrenia
• tryptophan

Notes