DRD2 antagonist/ClpP agonist ONC206

An orally bioavailable, selective bitopic dopamine receptor D2 (DRD2) antagonist and mitochondrial caseinolytic protease P (ClpP) agonist, with potential antineoplastic activity. Upon administration, DRD2 antagonist/ClpP agonist ONC206 targets, binds to and inhibits the activity of DRD2. This may inactivate Akt (protein kinase B) and extracellular signal-regulated kinase (ERK), which may result in inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt signal transduction pathway as well as the mitogen-activated protein kinase (MAPK)/ERK-mediated pathway. This may lead to the induction of tumor cell apoptosis mediated by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)/death receptor type 5 (DR5; TRAIL receptor 2) signaling in tumor cells. In addition, ONC206 targets and binds to ClpP and induces proteolysis. This may disrupt mitochondrial structure and function in tumor cells and lead to tumor cell death. DRD2, a G protein-coupled receptor (GPCR), is overexpressed in various malignancies. It is activated by dopamine produced by the tumor cells or present in the tumor microenvironment (TME) and plays an important role in the pro-survival and stress signaling pathways. ONC206 is able to cross the blood-brain barrier (BBB).