Szász Zsófia, Takács Angéla, Kalabay Márton, Bárány Péter, Czuczi Tamás, Csámpai Antal, Lajkó Eszter, Kőhidai László
Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, 1089, Hungary.
Department of Organic Chemistry, Institute of Chemistry, Eötvös Loránd University, Budapest, 1117, Hungary.
Sci Rep. 2025 May 7;15(1):15925. doi: 10.1038/s41598-025-00070-x.
Pancreatic ductal adenocarcinoma has a high mortality rate, with a 5-year survival rate of ~ 12%. Therefore, developing new targeted therapies is urgently needed. ONC-201, a promising candidate, is currently undergoing clinical trials. The main objective of the present work is to investigate the anti-tumour activity of ONC-201 and its two fluorinated analogues (TBP-134, TBP-135). The viability of two pancreatic adenocarcinoma cell lines (PANC-1, MIA PaCa-2) and three other tumour cell lines (A2058, EBC-1, COLO-205) was assessed after 72-hour treatment with drugs at 0.5, 10, and 25 µM. Significant antiproliferative effects were observed, with 0.5 µM TBP-134 achieving the highest potency, reducing cell viability to approximately 50%. None of the molecules exhibited significant cytotoxicity toward normal human dermal fibroblast cells or cardiomyocytes, indicating a selective anti-tumour profile. The analogues showed more effective results than ONC201 on PANC-1 cells (IC: 0.35 and 1.8 µM vs. IC: 6.1 µM, respectively). All analogues induced G2/M phase arrest followed by apoptosis in PANC-1 cells. The site of the fluorination influenced the mechanism of apoptotic action of these compounds. Overall, TBP-134 showed superior efficacy, making it a promising candidate for structural optimization within the imipridone family to develop more effective, selective treatments for pancreatic tumours.
胰腺导管腺癌死亡率很高，5年生存率约为12%。因此，迫切需要开发新的靶向治疗方法。有前景的候选药物ONC-201目前正在进行临床试验。本研究的主要目的是研究ONC-201及其两种氟化类似物（TBP-134、TBP-135）的抗肿瘤活性。在用0.5、10和25μM药物处理72小时后，评估了两种胰腺腺癌细胞系（PANC-1、MIA PaCa-2）和其他三种肿瘤细胞系（A2058、EBC-1、COLO-205）的活力。观察到显著的抗增殖作用，其中0.5μM TBP-134效力最高，将细胞活力降低至约50%。这些分子对正常人皮肤成纤维细胞或心肌细胞均未表现出显著的细胞毒性，表明具有选择性抗肿瘤特征。这些类似物在PANC-1细胞上显示出比ONC201更有效的结果（IC：分别为0.35和1.8μM，而ONC201为6.1μM）。所有类似物均诱导PANC-1细胞发生G2/M期阻滞并随后凋亡。氟化位点影响了这些化合物的凋亡作用机制。总体而言，TBP-134显示出卓越的疗效，使其成为咪吡啶酮家族中进行结构优化以开发更有效、更具选择性的胰腺肿瘤治疗药物的有前景的候选物。
