ONC206 is a dopamine D2-like receptor (DRD2/3/4) antagonist belonging to the imipridone class of drugs, with an IC50 of 0.21μM to 0.32μM [1]. Dopamine receptors belong to the G-protein coupled receptor family and play an important role in regulating cellular physiological functions. Antagonism of these receptors by ONC206 can interfere with the transmission of growth signals in tumor cells[2]. ONC206 has demonstrated potential in therapeutic research for various solid and hematological malignancies, including endometrial cancer, colorectal cancer, acute myeloid leukemia, etc[3].
In vitro, treatment of ARK1 and SPEC-2 cells with ONC206 (0-50μM) for 72 hours significantly inhibited cell proliferation in a dose-dependent manner via the DRD2/5 and TRAIL/DR5 pathways[4]. Treatment of U87 GBM cells with ONC206 (0.2μM) for 72 hours suppressed GBM cell proliferation, induced apoptosis, reduced c-myc protein level, inhibited glycolysis and oxidative phosphorylation, and activated the SOG metabolic pathway[5].
In vivo, intraperitoneal injection of ONC206 (100mg/kg) for 12 days in ARK1-luc cell xenograft mice significantly delayed tumor growth and disrupted the DRD2-mediated p38MAPK/ERK/PGC-1α network, leading to metabolic reprogramming, inhibition of glycolysis and oxidative phosphorylation [6]. Subcutaneous injection of ONC206 (80mg/kg) in Huh7 cells xenograft tumor mice significantly retarded tumor growth[7].
References:
[1] Staley A, Tucker K, Yin Y, et al. Highly potent dopamine receptor D2 antagonist ONC206 demonstrates anti-tumorigenic activity in endometrial cancer. Am J Cancer Res 2021, 11(11):5374-5387.
[2] Wang X, Wang ZB, Luo C, et al. The Prospective Value of Dopamine Receptors on Bio-Behavior of Tumor. J Cancer 2019, 10(7):1622-1632.
[3] Bonner ER, Waszak SM, Grotzer MA, et al. Mechanisms of imipridones in targeting mitochondrial metabolism in cancer cells. Neuro Oncol 2021, 23(4):542-556.
[4] Zhang Y, Huang Y, Yin Y, et al. ONC206, an Imipridone Derivative, Induces Cell Death Through Activation of the Integrated Stress Response in Serous Endometrial Cancer In Vitro. Front Oncol 2020, 10:577141.
[5] Ishida CT, Zhang Y, Bianchetti E, et al. Metabolic Reprogramming by Dual AKT/ERK Inhibition through Imipridones Elicits Unique Vulnerabilities in Glioblastoma. Clin Cancer Res 2018, 24(21):5392-5406.
[6] Paraghamian SE, Qiu J, Hawkins GM, et al. A novel dopamine receptor D2 antagonist (ONC206) potentiates the effects of olaparib in endometrial cancer. Cancer Biol Ther 2023, 24(1):2202104.
[7] Cao J, Cao F, Wang C, et al. ONC206 targeting ClpP induces mitochondrial dysfunction and protective autophagy in hepatocellular carcinoma cells. Neoplasia 2024, 55:101015.