Related Experiment Video
Updated: Apr 18, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity
Jessica Wagner1, Christina Leah Kline1, Richard S Pottorf2
1Hematology/Oncology Division and Penn State Hershey Cancer Institute, Penn State University, Hershey, PA, USA. Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medical Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
Abstract:
We previously identified TRAIL-inducing compound 10 (TIC10), also known as NSC350625 or ONC201, from a NCI chemical library screen as a small molecule that has potent anti-tumor efficacy and a benign safety profile in preclinical cancer models. The chemical structure that was originally published by Stahle, et. al. in the patent literature was described as an imidazo[1,2-a]pyrido[4,3-d]pyrimidine derivative. The NCI and others generally accepted this as the correct structure, which was consistent with the mass spectrometry analysis outlined in the publication by Allen et. al. that first reported the molecule's anticancer properties. A recent publication demonstrated that the chemical structure of ONC201 material from the NCI is an angular [3,4-e] isomer of the originally disclosed, linear [4,3-d] structure. Here we confirm by NMR and X-ray structural analysis of the dihydrochloride salt form that the ONC201 material produced by Oncoceutics is the angular [3,4-e] structure and not the linear structure originally depicted in the patent literature and by the NCI. Similarly, in accordance with our biological evaluation, the previously disclosed anti-cancer activity is associated with the angular structure and not the linear isomer. Together these studies confirm that ONC201, produced by Oncoceutics or obtained from the NCI, possesses an angular [3,4-e] structure that represents the highly active anti-cancer compound utilized in prior preclinical studies and now entering clinical trials in advanced cancers.
Insights
ONC201, a potent anti-cancer compound, has an angular [3,4-e] structure, not the previously reported linear isomer. This confirmed structure is responsible for its efficacy in preclinical cancer models and ongoing clinical trials.
Area of Science:
- Medicinal Chemistry
- Structural Biology
- Oncology
Background:
- TRAIL-inducing compound 10 (TIC10), also known as ONC201, was identified as a potent anti-cancer agent with a favorable safety profile.
- Initial reports described ONC201 as a linear imidazo[1,2-a]pyrido[4,3-d]pyrimidine derivative, consistent with mass spectrometry data.
- A recent study suggested that ONC201 from the National Cancer Institute (NCI) possesses an angular [3,4-e] isomeric structure.
Purpose of the Study:
- To definitively confirm the chemical structure of ONC201.
- To determine if the anti-cancer activity is associated with the linear or angular isomer.
- To validate the structure of ONC201 produced by Oncoceutics.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy.
- X-ray crystallographic analysis of the dihydrochloride salt form.
- Comparison with previously reported mass spectrometry and biological data.
Main Results:
- NMR and X-ray analysis confirmed that ONC201 produced by Oncoceutics has the angular [3,4-e] structure.
- The linear [4,3-d] structure initially depicted in patent literature and by the NCI was found to be incorrect for the active compound.
- Biological evaluation indicated that the anti-cancer activity resides in the angular isomer.
Conclusions:
- ONC201 possesses an angular [3,4-e] structure, which is the active anti-cancer compound.
- This confirmed structure is consistent between material produced by Oncoceutics and obtained from the NCI.
- The angular ONC201 structure is the basis for its preclinical efficacy and progression into clinical trials for advanced cancers.
More Related Videos
09:20Preclinical Assessment of the Bioactivity of the Anticancer Coumarin OT48 by Spheroids, Colony Formation Assays, and Zebrafish Xenografts
Published on: June 26, 2018
06:00Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics
Published on: May 14, 2016
Related Concept Videos
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
02:53Adaptive Mechanisms in Cancer Cells
02:49Cancer Therapies
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...
02:49Cancer Therapies
02:18Cancer
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...