Imipridones – A Novel Class of Anti-Cancer Molecules

ONC201

ONC201 is the founding member of the imipridone class of small molecule. ONC201 acts as a bitopic antagonist of the G protein-coupled receptor (GPCR) dopamine receptor D2 (DRD2) and an allosteric agonist of the mitochondrial protease caseinolytic protease P (ClpP). Its chemical attributes enable oral bioavailability that achieves therapeutic concentrations and wide distribution throughout the body to target tissues, including brain, bone marrow and lymph nodes. ONC201 has demonstrated compelling safety with a therapeutic pharmacokinetic profile, induction of pharmacodynamic markers, and preliminary efficacy in Phase I and II clinical trials across a range of DRD2/ClpP dysregulated tumors, including high-grade gliomas, adrenal tumors and endometrial cancer.

Imipridones prioritized for clinical development in oncology.

ONC206

ONC206 acts as a bitopic DRD2 antagonist and ClpP agonist that exhibits enhanced non-competitive effects, high specificity, nanomolar potency, and disruption of DRD2 homodimers. ONC206 has highly potent activity in preclinical models of difficult-to-treat neuroendocrine tumors and high-grade gliomas. Downstream of target engagement, ONC206 exhibits a mechanism of action similar to that of ONC201, involving activation of the integrated stress response and induction of TRAIL. First in human dose of ONC206 has been administered for patients with advanced, primary central nervous system tumors. More information on the ONC206 clinical trial can be found on clinicaltrials.gov.

ONC212

ONC212 is an agonist of the orphan GPCR tumor suppressor GPR132, as well as an agonist of ClpP. Similar to the downstream effects of ONC201 and ONC206, it activates the integrated stress response and induces TRAIL-mediated apoptosis in tumor cells. ONC212 has broad-spectrum activity across both solid tumors and hematological malignancies, including pancreatic cancer and leukemias prioritized as target clinical indications that exhibit high GPR132 and/or ClpP expression. IND-enabling studies for ONC212 are ongoing and Phase I clinical trials in pancreatic cancer and acute leukemia are planned.