NCIt definition : 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).;
Semantic type(s)