title: Antitumour agents as inhibitors of tryptophan 2,3-dioxygenase.
abstract: The involvement of tryptophan 2,3-dioxygenase (TDO) in cancer biology has recently been described, with the enzyme playing an immunomodulatory role, suppressing antitumour immune responses and promoting tumour cell survival and proliferation. This finding reinforces the need for specific inhibitors of TDO that may potentially be developed for therapeutic use. In this work we have screened ~2800 compounds from the library of the National Cancer Institute USA and identified seven potent inhibitors of TDO with inhibition constants in the nanomolar or low micromolar range. All seven have antitumour properties, killing various cancer cell lines. For comparison, the inhibition potencies of these compounds were tested against IDO and their inhibition constants are reported. Interestingly, this work reveals that NSC 36398 (dihydroquercetin, taxifolin), with an in vitro inhibition constant of ~16 μM, is the first TDO-selective inhibitor reported.
authors.affiliation: EaStCHEM School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, UK.
authors.forename: Georgios
authors.initials: G
authors.lastname: Pantouris
authors.affiliation: EaStCHEM School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, UK. Electronic address: C.G.Mowat@ed.ac.uk.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mowat
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002396:Catechols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology*; D006801:Humans; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D002396:Catechols; D002867:Chromones; C519302:NSC 36398; D011794:Quercetin; C003377:taxifolin; D014366:Tryptophan Oxygenase
keywords: Cancer; IDO; KMO; Kynurenine pathway; NCI; National Cancer Institute USA; TDO; Tryptophan 2,3-dioxygenase; human indoleamine 2,3-dioxygenase; human tryptophan 2,3-dioxygenase; kynurenine 3-monoxygenase