ONC206, a
dopamine receptor D2 (DRD2) antagonist and imipridone, is a chemically modified derivative of
ONC201. Recently,
ONC206 and other imipridones were identified as activators of the mitochondrial
protease ClpP, inducing downstream pathways that allow them to selectively target
cancer cells. Clinical trials showed that
ONC201, the first in class imipridone, was well tolerated and exhibited
tumor regression in some solid
tumors. Our goal was to evaluate the effect of
ONC206 on cell proliferation and
tumor growth in
ovarian cancer cell lines and in a transgenic mouse model of high grade serous
ovarian cancer (KpB model).
ONC206 was more potent than
ONC201 in inhibiting cell proliferation, as evidenced by a 10-fold decrease in IC50 for the SKOV3 and OVCAR5 cell lines. This was accompanied by the results that
ONC206 significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, caused cellular stress, and inhibited adhesion and invasion in vitro. Treatment of obese and non-obese KpB mice with
ONC206 elevated Bip and ClpP expression and reduced KI67, BCL-XL and DRD2 expression in the ovarian
tumors. Our findings demonstrate that
ONC206 has anti-tumorigenic effects in
ovarian cancer as previously demonstrated by
ONC201 but appears to be as well tolerated and more potent. Thus,
ONC206 deserves further evaluation in clinical trials.