title: Targeting key dioxygenases in tryptophan-kynurenine metabolism for immunomodulation and cancer chemotherapy.
abstract: Tryptophan to kynurenine metabolism is controlled by three distinct dioxygenase enzymes: tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase 1 (IDO1), and indoleamine 2,3-dioxygenase 2 (IDO2). Collectively, the activity of these enzymes contributes to tumour immune tolerance and immune dysregulation in a variety of disease pathologies, including cancer. Whereas IDO1 inhibitor drug design has been the focus of study for more than two decades (with novel compounds currently in Phase II clinical trials), only recently have the roles of TDO and IDO2 been elucidated in immunosuppression. Consequently, little comparative work on inhibitor cross-reactivity and selectivity has been performed. Here, we provide an overview of the current and future drug discovery landscape for targeting TDO, IDO1, and IDO2 (individually and collectively) for pharmacological intervention.
authors.affiliation: School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Christopher J D
authors.initials: CJ
authors.lastname: Austin
authors.affiliation: School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: lou.rendina@sydney.edu.au.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Rendina
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D020134:Catalytic Domain; D049308:Dioxygenases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D055808:Drug Discovery; D006801:Humans; D007155:Immunologic Factors / Q000737:chemistry / Q000627:therapeutic use*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism*; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C576710:IDO1 protein, human; C576711:IDO2 protein, human; D007155:Immunologic Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D014364:Tryptophan; D049308:Dioxygenases; D014366:Tryptophan Oxygenase