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.
Maria Winters  1 ,  James B DuHadaway  2 ,  Khoa N Pham  3 ,  Ariel Lewis-Ballester  3 ,  Shorouk Badir  1 ,  Jenny Wai  1 ,  Eesha Sheikh  1 ,  Syun-Ru Yeh  3 ,  George C Prendergast  4 ,  Alexander J Muller  5 ,  William P Malachowski  6
Affiliations
  • 1. Department of Chemistry, Bryn Mawr College, Bryn Mawr, PA, 19010, USA.
  • 2. Lankenau Institute for Medical Research, 100 Lancaster Ave, Wynnewood, PA 19096, USA.
  • 3. Department of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, United States.
  • 4. Lankenau Institute for Medical Research, 100 Lancaster Ave, Wynnewood, PA 19096, USA; Department of Pathology, Anatomy & Cell Biology and, Philadelphia, PA 19104, USA; Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19104, USA. Electronic address: [email protected].
  • 5. Lankenau Institute for Medical Research, 100 Lancaster Ave, Wynnewood, PA 19096, USA; Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19104, USA. Electronic address: [email protected].
  • 6. Department of Chemistry, Bryn Mawr College, Bryn Mawr, PA, 19010, USA. Electronic address: [email protected].
PMID: 30469041 DOI: 10.1016/j.ejmech.2018.11.010
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.