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. Epub 2013 Nov 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Hydrazines / chemistry
  • Hydrazines / pharmacology*
  • Immune System / drug effects
  • Immune System / enzymology*
  • Immune System / metabolism
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Hydrazines
  • IDO1 protein, mouse
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Recombinant Proteins
  • indoleamine 2,3-dioxygenase 1, human