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.