title: The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity.
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.
authors.affiliation: Hematology/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.
authors.forename: Jessica
authors.initials: J
authors.lastname: Wagner
authors.affiliation: Hematology/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.
authors.forename: Christina Leah
authors.initials: CL
authors.lastname: Kline
authors.affiliation: Provid Pharmaceuticals, Inc., Monmouth Junction, NJ, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Pottorf
authors.affiliation: Provid Pharmaceuticals, Inc., Monmouth Junction, NJ, USA.
authors.forename: Bhaskara Rao
authors.initials: BR
authors.lastname: Nallaganchu
authors.affiliation: Provid Pharmaceuticals, Inc., Monmouth Junction, NJ, USA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Olson
authors.affiliation: Hematology/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.
authors.forename: David T
authors.initials: DT
authors.lastname: Dicker
authors.affiliation: Oncoceutics, Inc., Hummelstown, PA, USA.
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Allen
authors.affiliation: Hematology/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.
authors.forename: Wafik S
authors.initials: WS
authors.lastname: El-Deiry
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles; D008279:Magnetic Resonance Imaging; D013058:Mass Spectrometry; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011725:Pyridines; D011743:Pyrimidines; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D007093:Imidazoles; D011725:Pyridines; D011743:Pyrimidines; C585684:TIC10 compound