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


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.
Costantino
Gabriele
G
Università degli Studi di Parma, Dipartimento Farmaceutico, Via GP Usberti 27/A-Campus Universitario, 43100 Parma, Italy. gabriele.costantino@unipr.it
D000818:Animals; D016503:Drug Delivery Systems; D055808:Drug Discovery; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy / Q000503:physiopathology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology*; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology*; D014364:Tryptophan / Q000378:metabolism
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D014364:Tryptophan