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


CONCLUSIONS
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.
Departments of Medicine, Genetics, and Pharmacology, Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia, 19104, PA, USA. joshjea@gmail.com.|Current affiliation: Oncoceutics, Inc., Hummelstown, PA, USA. joshjea@gmail.com.
Joshua E
JE
Allen
Departments of Medicine, Genetics, and Pharmacology, Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia, 19104, PA, USA. g.krigsfeld@gmail.com.
Gabriel
G
Krigsfeld
Departments of Medicine, Genetics, and Pharmacology, Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia, 19104, PA, USA. luveroni@gmail.com.
Luv
L
Patel
Departments of Medicine, Genetics, and Pharmacology, Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia, 19104, PA, USA. patrick.mayes@gmail.com.
Patrick A
PA
Mayes
Departments of Medicine, Genetics, and Pharmacology, Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia, 19104, PA, USA. david.dicker@fccc.edu.|Department of Medical Oncology and Molecular Therapeutics Program, Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Fox Chase Cancer Center, Philadelphia, 19111, PA, USA. david.dicker@fccc.edu.
David T
DT
Dicker
Department of Pathology, Program in Molecular Biology and Genetics, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA. wug@karmanos.org.
Gen Sheng
GS
Wu
Departments of Medicine, Genetics, and Pharmacology, Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia, 19104, PA, USA. wafik.eldeiry@fccc.edu.|Department of Medical Oncology and Molecular Therapeutics Program, Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Fox Chase Cancer Center, Philadelphia, 19111, PA, USA. wafik.eldeiry@fccc.edu.
Wafik S
WS
El-Deiry
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D017930:Genes, Reporter; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles; D008156:Luciferases / Q000378:metabolism; D009153:Mutagens / Q000633:toxicity; D011401:Promoter Regions, Genetic / Q000235:genetics; D011725:Pyridines; D011743:Pyrimidines; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D000970:Antineoplastic Agents; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D006576:Heterocyclic Compounds, 4 or More Rings; D007093:Imidazoles; D009153:Mutagens; D011725:Pyridines; D011743:Pyrimidines; D054852:Small Molecule Libraries; D053221:TNF-Related Apoptosis-Inducing Ligand; C585684:TIC10 compound; D008156:Luciferases