Diaryl hydroxylamines as pan or dual inhibitors of indoleamine 2,3-dioxygenase-1, indoleamine 2,3-dioxygenase-2 and tryptophan dioxygenase

Eur J Med Chem. 2019 Jan 15:162:455-464. doi: 10.1016/j.ejmech.2018.11.010. Epub 2018 Nov 14.

Abstract

Tryptophan (Trp) catabolizing enzymes play an important and complex role in the development of cancer. Significant evidence implicates them in a range of inflammatory and immunosuppressive activities. Whereas inhibitors of indoleamine 2,3-dioxygenase-1 (IDO1) have been reported and analyzed in the clinic, fewer inhibitors have been described for tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase-2 (IDO2) which also have been implicated more recently in cancer, inflammation and immune control. Consequently the development of dual or pan inhibitors of these Trp catabolizing enzymes may represent a therapeutically important area of research. This is the first report to describe the development of dual and pan inhibitors of IDO1, TDO and IDO2.

Keywords: Antitumor therapy; Diaryl oalkylhydroxylamines; Dual inhibitor; IDO1 inhibition; IDO2 inhibition; Pan inhibition; TDO inhibition.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents
  • Antineoplastic Agents
  • Humans
  • Hydroxylamines / pharmacology*
  • Immunologic Factors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
  • Tryptophan Oxygenase / antagonists & inhibitors*

Substances

  • Anti-Inflammatory Agents
  • Antineoplastic Agents
  • Hydroxylamines
  • IDO1 protein, human
  • IDO2 protein, human
  • Immunologic Factors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Tryptophan Oxygenase