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.
ONC206是一种多巴胺 D2 样受体（DRD2/3/4）拮抗剂，属于依米立酮类药物，IC50为0.21μM-0.32μM[1]。多巴胺受体属于G蛋白偶联受体家族，在细胞生理功能调节中发挥重要作用，ONC206对其拮抗可干扰肿瘤细胞生长信号的传递[2]。ONC206在多种实体瘤和血液肿瘤治疗研究中展现潜力，包括子宫内膜癌、结直肠癌、急性髓系白血病等[3]。
在体外，ONC206（0-50μM）分别处理ARK1和SPEC-2细胞72小时，通过DRD2/5和TRAIL/DR5 通路显著抑制细胞增殖并呈现出剂量依赖性作用 [4]。使用ONC206（0.2μM）处理U87细胞72h，可抑制GBM细胞增殖与诱导凋亡，降低c-myc蛋白水平，抑制糖酵解和氧化磷酸化，激活SOG代谢通路 [5]。
在体内，ONC206（100mg/kg）通过腹腔注射治疗ARK1-luc细胞异种移植小鼠12天，显著延迟了小鼠肿瘤的生长，并破坏DRD2介导的p38MAPK/ERK/PGC-1α网络导致代谢重编程、糖酵解和氧化磷酸化抑制[6]。ONC206（80mg/kg）通过皮下注射用于治疗通过Huh7 细胞异种移植肿瘤小鼠，能够显著延缓肿瘤生长[7]。