Tryptophan 2,3-dioxygenase (TDO) Inhibitors. 3-(2-(pyridyl)ethenyl)indoles as Potential Anticancer Immunomodulators

J Med Chem. 2011 Aug 11;54(15):5320-34. doi: 10.1021/jm2006782. Epub 2011 Jul 18.


Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance. IDO inhibition is thus an active area of research in drug development. Recently, our group has shown that tryptophan 2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is also expressed in many tumors and that this expression prevents tumor rejection by locally depleting tryptophan. Herein, we report a structure-activity study on a series of 3-(2-(pyridyl)ethenyl)indoles. More than 70 novel derivatives were synthesized, and their TDO inhibitory potency was evaluated. The rationalization of the structure-activity relationships (SARs) revealed essential features to attain high TDO inhibition and notably a dense H-bond network mainly involving His(55) and Thr(254) residues. Our study led to the identification of a very promising compound (58) displaying good TDO inhibition (K(i) = 5.5 μM), high selectivity, and good oral bioavailability. Indeed, 58 was chosen for preclinical evaluation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Biological Availability
  • Cell Line
  • Drug Design
  • Enzyme Inhibitors / therapeutic use*
  • Humans
  • Immunologic Factors / pharmacology*
  • Indoles / chemical synthesis
  • Indoles / pharmacology*
  • Indoles / therapeutic use
  • Kinetics
  • Mice
  • Neoplasms / enzymology
  • Structure-Activity Relationship
  • Tryptophan Oxygenase / antagonists & inhibitors*


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Immunologic Factors
  • Indoles
  • Tryptophan Oxygenase