ONC212

ONC212 is a potent imipridone small-molecule (and fluorinated imipridone analog of ONC201) that acts as a dual agonist of the mitochondrial protease ClpP and the orphan GPCR GPR132, provoking mitochondrial dysfunction, integrated stress response, and apoptotic cell death, particularly in acute leukemia and solid tumor models. By targeting the mitochondrial protease ClpP, this engagement disrupts mitochondrial function, impairs oxidative phosphorylation and contributes to its anti-tumor activity across diverse preclinical cancer models. Acting as an agonist of the orphan G protein-coupled receptor GPR132, triggering downstream Gαq signaling and the integrated stress response, contributes to its pronounced anti-leukemic effects, particularly in acute myeloid leukemia models.