Potent Anti-Leukemic Effects of Small Molecule ONC212, a Member of the Imipridone Class of Anti-Cancer Compounds

ONC201, the founding member of the imipridone class of anti-cancer compounds, is a highly selective small molecule GPCR antagonist that is in Phase I/II advanced cancer clinical trials. In this study, we evaluated the anti-cancer effects of ONC212, an ONC201 analogue that possess the same unique core chemical structure shared by imipridones.

The in vitro efficacy of ONC212 was assessed in the Genomics of Drug Sensitivity in Cancer collection of cell lines (>1,000 cell lines). Cell viability assays were performed to generate dose responses curves at concentrations from 78nM upto 20uM and at 72 hours post-treatment. ONC212 was broadly efficacious across most solid tumors and hematological malignancies in the low nanomolar range. Ranking the ONC212 sensitivity dataset revealed that leukemia is the most responsive tumor type based on completeness of response (area under the dose-response curve, AUC).

ONC212 was tested in 65 leukemia cell lines in this study that is comprised of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML) and hairy cell leukemia. ONC212 demonstrated broad spectrum anti-leukemic activity and was equally efficacious across all leukemia subtypes tested, in terms of AUC. Most cell lines (63/65) were responsive to ONC212 with GI50 ranging from <78nM to 312nM. Within ALL, both B-cell and T-cell ALL were highly sensitive to ONC212. ONC212 reduced cell viability in AML independent of complex karyotypes that are associated with poor clinical prognoses.

Thus, ONC212 possesses robust anti-leukemic activity irrespective of subtype and provides further validation of the anti-cancer efficacy of the novel imipridone class of small molecules.