ONC206 is a DRD2 antagonist and ClpP agonist with nanomolar potency that demonstrates enhanced non-competitive DRD2 antagonism relative to ONC201, and disruption of DRD2 homodimers. ONC206 exhibits a distinct gene expression profile as well as single agent and combinatorial efficacy with ONC201 in cells with acquired resistance to ONC201. ONC206 is effective in preclinical models of difficult-to-treat neuroendocrine tumors and high-grade gliomas. It affects some of the same downstream pathways as ONC201, including activation of the integrated stress response and inhibition of Ras signaling, leading to selective killing of tumor cells.
The first-in-human clinical trial for adults with recurrent primary central nervous system tumors is ongoing at the National Institute of Health (NCT04541082).