Discovery and characterisation of hydrazines as inhibitors of the immune suppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO1)

  • Bioorg Med Chem. 2013 Dec 15;21(24):7595-603. doi: 10.1016/j.bmc.2013.10.037.
Sai-Parng S Fung  1 ,  Haiyan Wang ,  Petr Tomek ,  Christopher J Squire ,  Jack U Flanagan ,  Brian D Palmer ,  David J A Bridewell ,  Sofian M Tijono ,  Joanne F Jamie ,  Lai-Ming Ching
Affiliations
  • 1. 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.
PMID: 24262887 DOI: 10.1016/j.bmc.2013.10.037
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.

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.
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