Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway

Mol Cancer. 2015 May 1;14:99. doi: 10.1186/s12943-015-0346-9.


Background: We previously reported the identification of ONC201/TIC10, a novel small molecule inducer of the human TRAIL gene that improves efficacy-limiting properties of recombinant TRAIL and is in clinical trials in advanced cancers based on its promising safety and antitumor efficacy in several preclinical models.

Methods: We performed a high throughput luciferase reporter screen using the NCI Diversity Set II to identify TRAIL-inducing compounds.

Results: Small molecule-mediated induction of TRAIL reporter activity was relatively modest and the majority of the hit compounds induced low levels of TRAIL upregulation. Among the candidate TRAIL-inducing compounds, TIC9 and ONC201/TIC10 induced sustained TRAIL upregulation and apoptosis in tumor cells in vitro and in vivo. However, ONC201/TIC10 potentiated tumor cell death while sparing normal cells, unlike TIC9, and lacked genotoxicity in normal fibroblasts. Investigating the effects of TRAIL-inducing compounds on cell signaling pathways revealed that TIC9 and ONC201/TIC10, which are the most potent inducers of cell death, exclusively activate Foxo3a through inactivation of Akt/ERK to upregulate TRAIL and its pro-apoptotic death receptor DR5.

Conclusion: These studies reveal the selective activity of ONC201/TIC10 that led to its selection as a lead compound for this novel class of antitumor agents and suggest that ONC201/TIC10 is a unique inducer of the TRAIL pathway through its concomitant regulation of the TRAIL ligand and its death receptor DR5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / metabolism
  • Genes, Reporter
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Humans
  • Imidazoles
  • Luciferases / metabolism
  • Mutagens / toxicity
  • Promoter Regions, Genetic / genetics
  • Pyridines
  • Pyrimidines
  • Signal Transduction / drug effects*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Transcription, Genetic / drug effects
  • Up-Regulation / drug effects


  • Antineoplastic Agents
  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Heterocyclic Compounds, 4 or More Rings
  • Imidazoles
  • Mutagens
  • Pyridines
  • Pyrimidines
  • Small Molecule Libraries
  • TNF-Related Apoptosis-Inducing Ligand
  • TIC10 compound
  • Luciferases