title: Discovery and characterisation of hydrazines as inhibitors of the immune suppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO1).
abstract: Screening of a fragment library identified 2-hydrazinobenzothiazole as a potent inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme expressed by tumours that suppresses the immune system. Spectroscopic studies indicated that 2-hydrazinobenzothiazole interacted with the IDO1 haem and in silico docking predicted that the interaction was through hydrazine. Subsequent studies of hydrazine derivatives identified phenylhydrazine (IC50=0.25 ± 0.07 μM) to be 32-fold more potent than 2-hydrazinobenzothiazole (IC50=8.0 ± 2.3 μM) in inhibiting rhIDO1 and that it inhibited cellular IDO1 at concentrations that were noncytotoxic to cells. Here, phenylhydrazine is shown to inhibit IDO1 through binding to haem.
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Victoria St. West, Auckland, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Victoria St. West, Auckland, New Zealand.
authors.forename: Sai-Parng S
authors.initials: SP
authors.lastname: Fung
authors.forename: Haiyan
authors.initials: H
authors.lastname: Wang
authors.forename: Petr
authors.initials: P
authors.lastname: Tomek
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Squire
authors.forename: Jack U
authors.initials: JU
authors.lastname: Flanagan
authors.forename: Brian D
authors.initials: BD
authors.lastname: Palmer
authors.forename: David J A
authors.initials: DJ
authors.lastname: Bridewell
authors.forename: Sofian M
authors.initials: SM
authors.lastname: Tijono
authors.forename: Joanne F
authors.initials: JF
authors.lastname: Jamie
authors.forename: Lai-Ming
authors.initials: LM
authors.lastname: Ching
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology*; D007107:Immune System / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D006834:Hydrazines; C576710:IDO1 protein, human; C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011994:Recombinant Proteins
keywords: 1-MT; 1-methyl-tryptophan; DSF; Fragment screen; Hydrazine; IDO1; Indoleamine 2,3-dioxygenase 1; Tumour immunity; differential scanning fluorimetry; indoleamine 2,3-dioxygenase 1