ONC206

ONC206 is an analogue of TRAIL inducer ONC201 and is a selective antagonist of the D2-like dopamine receptors (DRD2/3/4) at nanomolar concentrations. ONC206 also has broad-spectrum anti-tumor activity. ONC206 (Oncoceutics) is an imipiridone with nanomolar potency and analogue of ONC201, a selective dopamine receptor D2 (DRD2) antagonist currently being investigated in phase II clinical trials for serous endometrial cancer (SEC) . ONC206 inhibited cellular proliferation in a dose-dependent manner and was more potent than ONC201 in the ARK1 (IC50 = 0.33 M vs. IC50 = 1.59uM) and SPEC-2 (IC50 = 0.24uM vs. IC50 = 0.81uM) cell lines. Treatment with ONC206 resulted in induction of ROS production and reduction of mitochondrial membrane potential, accompanied by an increase in cleaved caspase-3 and caspase-9 activity (p < 0.01) . ONC206 also significantly inhibited cellular adhesion and migration in both cell lines (p < 0.01) . Pretreatment with the stress inhibitor N-acetylcysteine (NAC) significantly attenuated the efficacy of ONC206 on cell proliferation, ROS production and cellular invasion. ONC206 demonstrates nanomolar potency for the inhibition of proliferation in SEC cells. ONC206 (100 mg/kg; p.o.; every 10 days) reduces obviously tumor growth inhibition.