Therapeutic Approach

Oncoceutics is developing a new class of safe and effective cancer therapies called imipridones. Imipridones have a unique three-ring tri-heterocyclic core structure and target G protein-coupled receptors (GPCRs), as well as mitochondrial caseinolytic protease P (ClpP), that are dysregulated in many forms of human cancer and other diseases. The imipridone chemical scaffold provides an opportunity to target GPCRs and ClpP with tunable specificity and modality, which enables vast therapeutic potential for many cancers and other diseases through selective modulation of distinct downstream mechanisms.

ONC201 is the founding member of the imipridone class of anti-cancer small molecules that selectively targets DRD2 as a bitopic antagonist and ClpP as an allosteric agonist. Downstream of target engagement, the molecule causes tumor cells to activate the integrated stress response, inhibit oxidative phosphorylation, degrade c-Myc, inactivate Ras signaling, and induce DR5/TRAIL. These effects trigger antiproliferative, cell cycle arrest, and/or pro-apoptotic effects in tumor cells in a cellular context-dependent manner.

ONC201-mediated DRD2 antagonism and ClpP agonism controls a network of downstream signaling pathways that cancer cells rely for survival and dissemination.

At a event hosted by Oncoceutics, Dr. Silvio Gutkind of UC San Diego, Dr. Keith Flaherty of Massachusetts General Hospital, and Dr. Joshua Allen of Oncoceutics spoke about the interaction between ONC201 and the DRD2, and the downstream pathways that interaction controls.