ONC201 is an orally active small molecule compound belonging to the imipridone class and acts as a selective antagonist of the dopamine D2/3 receptors (DRD2/3)[1]. DRD2/3, which are G protein-coupled receptors (GPCRs), are overexpressed in various tumor cells[2]. ONC201 induces tumor cell apoptosis by antagonizing DRD2/3 and activating the ClpP protease, and further enhances its antitumor effects by activating the immune system. This multi-target mechanism of action enables ONC201 to exhibit extensive anti-tumor activity in various tumor types[3]. ONC201 is commonly used in cancer research, particularly in the study of various solid tumors and hematological malignancies[4][5].
In vitro,ONC201 (5μM, 72h) exposure causes a dose-dependent increase in TRAIL mRNA and induces TRAIL protein localization on the cell surface of HCT116 human colon cancer cells in a p53-independent manner, while also inducing TRAIL-mediated apoptosis[6]. Combination of L_GEM and ONC201(200nM,72h) arrests MIA PaCa-2 cells in the G2 phase and induces apoptosis[7].
In vivo, combinated treatment of ONC201(15mg/kg; three times a week for two weeks) and L_GEM reduced the tumor size, inhibited the expression of p-ERK and p-AKT and upregulated the expression of cleaved Caspase 3 of tumor tissues in KPC tumor-bearing syngeneic mice[7].
References:
[1] Stein, M. N., Bertino, J. R., Kaufman, H. L., Mayer, T., Moss, R., Silk, A., Chan, N., Malhotra, J., Rodriguez, L., Aisner, J., Aiken, R. D., Haffty, B. G., DiPaola, R. S., Saunders, T., Zloza, A., Damare, S., Beckett, Y., Yu, B., Najmi, S., Gabel, C., … Mehnert, J. M. (2017). First-in-Human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors. Clinical cancer research : an official journal of the American Association for Cancer Research, 23(15), 4163–4169.
[2] Bonner, E. R., Waszak, S. M., Grotzer, M. A., Mueller, S., & Nazarian, J. (2021). Mechanisms of imipridones in targeting mitochondrial metabolism in cancer cells. Neuro-oncology, 23(4), 542–556.
[3] Prabhu, V. V., Morrow, S., Rahman Kawakibi, A., Zhou, L., Ralff, M., Ray, J., Jhaveri, A., Ferrarini, I., Lee, Y., Parker, C., Zhang, Y., Borsuk, R., Chang, W. I., Honeyman, J. N., Tavora, F., Carneiro, B., Raufi, A., Huntington, K., Carlsen, L., Louie, A., … El-Deiry, W. S. (2020). ONC201 and imipridones: Anti-cancer compounds with clinical efficacy. Neoplasia (New York, N.Y.), 22(12), 725–744.
[4] Allen, J. E., Prabhu, V. V., Talekar, M., van den Heuvel, A. P., Lim, B., Dicker, D. T., Fritz, J. L., Beck, A., & El-Deiry, W. S. (2015). Genetic and Pharmacological Screens Converge in Identifying FLIP, BCL2, and IAP Proteins as Key Regulators of Sensitivity to the TRAIL-Inducing Anticancer Agent ONC201/TIC10. Cancer research, 75(8), 1668–1674.
[5] Ishizawa, J., Kojima, K., Chachad, D., Ruvolo, P., Ruvolo, V., Jacamo, R. O., Borthakur, G., Mu, H., Zeng, Z., Tabe, Y., Allen, J. E., Wang, Z., Ma, W., Lee, H. C., Orlowski, R., Sarbassov, dosD., Lorenzi, P. L., Huang, X., Neelapu, S. S., McDonnell, T., … Andreeff, M. (2016). ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies. Science signaling, 9(415), ra17.
[6] Allen, J. E., Krigsfeld, G., Mayes, P. A., Patel, L., Dicker, D. T., Patel, A. S., Dolloff, N. G., Messaris, E., Scata, K. A., Wang, W., Zhou, J. Y., Wu, G. S., & El-Deiry, W. S. (2013). Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects. Science translational medicine, 5(171), 171ra17.
[7] Kumar, V., Sethi, B., Staller, D. W., Shrestha, P., & Mahato, R. I. (2024). Gemcitabine elaidate and ONC201 combination therapy for inhibiting pancreatic cancer in a KRAS mutated syngeneic mouse model. Cell death discovery, 10(1), 158.
ONC201是一种具有口服活性的小分子化合物，属于imipridone类化合物，是多巴胺D2/3受体（DRD2/3）的选择性拮抗剂[1]。DRD2/3是G蛋白偶联受体（GPCR），在多种肿瘤细胞中过表达[2]。ONC201通过拮抗DRD2/3和激活ClpP蛋白酶诱导肿瘤细胞凋亡，并通过激活免疫系统进一步增强抗肿瘤效果, 这种多靶点作用机制使ONC201在多种肿瘤类型中表现出广泛的抗肿瘤活性[3]。ONC201通常用于癌症研究，特别是针对多种实体瘤和血液系统恶性肿瘤的研究[4][5]。
体外实验中，ONC201（5μM，72小时）处理导致HCT116人结肠癌细胞中TRAIL mRNA的含量呈剂量依赖性增加，并以不依赖p53的方式诱导TRAIL蛋白在细胞表面的定位，同时还诱导TRAIL介导的凋亡[6]。ONC201（200nM，72小时）与L_GEM的联合处理使MIA PaCa-2细胞停滞在G2期，并诱导凋亡[7]。
体内实验中，ONC201（15mg/kg，每周三次，持续两周）与L_GEM的联合治疗在KPC肿瘤小鼠模型中减少了肿瘤大小，抑制了肿瘤组织中p-ERK和p-AKT的表达，并上调了cleaved Caspase 3的表达[7]。