In vitro evaluation of small molecules and peptide-based conjugates for targeted tumour therapy in pancreatic tumour cell lines
Szász Adrienn Zsófia
Gyógyszertudományok és Egészségügyi Technológiák Tagozat
Dr. Zelkó Romána
SE NET Zöld előadóterem
2025-08-06 10:00:00
Modern Trends in Pharmaceutical Scientific Research
Dr. Antal István
Dr. Kőhidai László és Dr. Lajkó Eszter
Dr. Zelles Tibor
Dr. Turiák Lilla
Dr. Tábi Tamás
Dr. Dunkel Petra Zsófia
Dr. Soós András Áron
Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of approximately 11%. This poor prognosis is paired with the lack of available targeted therapy treatment options. Therefore, this thesis explores the anti-tumour effects of ONC201, its fluorinated analogues, and daunorubicin-containing peptide conjugates on the PANC-1 PDAC cell line. Furthermore, the thesis also presents the synergistic effect of ONC201 in combination with bortezomib on the A2058 melanoma cell line.
The research shows that adding fluorine and chlorine atoms significantly enhances the potency of the compounds. The thesis reveals that the para-fluorinated ONC201 analogue, TBP-134, had an IC50 value of 0.35 μM, much lower than ONC201's 6.1 μM. Among the peptide-drug conjugates (PDC), Conj16 with para-chloro-phenylalanine was the most effective. The compounds were also assessed for selectivity and safety: ONC201 analogues had minimal antiproliferative effects on healthy fibroblasts and no cytotoxicity at effective concentrations, while the conjugates showed no cardiotoxicity at 10 μM. This selective targeting of tumour cells over healthy enhances the therapeutic index and reduces potential side effects.
Additionally, the thesis examines how these molecules exert their anti-tumour effects. ONC201 and its analogues induce apoptosis through different mechanisms. Specifically, both ONC201 and TBP-135 activate apoptosis via both the extrinsic pathway through DR5 and the intrinsic pathway, while TBP-134 predominantly triggers the intrinsic pathway of apoptosis. Moreover, ONC201 could act synergistically through DR5 with bortezomib on A2058 cells, suggesting that the analogues may have the same effect. Conj16, with its chlorinated amino acid, demonstrated increased cellular uptake, induction of cellular senescence and as well as the ability to induce apoptosis. The senescent state was achieved through the downregulation of CCNA1 and upregulation of CDKN1A.
In conclusion, the thesis presents two promising approaches for targeting PDAC: small molecules and PDCs, both improved by halogenation. These findings offer significant hope for developing more effective, targeted therapies for PDAC, a disease with few current treatment options. The research aligns with the broader trend in oncology towards personalised and targeted therapies.
