A New Oxadiazole-Based Topsentin Derivative Modulates Cyclin-Dependent Kinase 1 Expression and Exerts Cytotoxic Effects on Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal form of cancer characterizedby drug resistance, urging new therapeutic strategies. In recent years, protein kinases have emergedas promising pharmacological targets for the treatment of several solid and hematological tumors.Interestingly, cyclin-dependent kinase 1 (CDK1) is overexpressed in PDAC tissues and has beencorrelated to the aggressive nature of these tumors because of its key role in cell cycle progressionand resistance to the induction of apoptosis. For these reasons, CDK1 is one of the main causesof chemoresistance, representing a promising pharmacological target. In this study, we report thesynthesis of new 1,2,4-oxadiazole compounds and evaluate their ability to inhibit the cell growth ofPATU-T, Hs766T, and HPAF-II cell lines and a primary PDAC cell culture (PDAC3). Compound 6bwas the most active compound, with IC50 values ranging from 5.7 to 10.7 M. Molecular dockingof 6b into the active site of CDK1 showed the ability of the compound to interact effectively withthe adenosine triphosphate binding pocket. Therefore, we assessed its ability to induce apoptosis(which increased 1.5- and 2-fold in PATU-T and PDAC3 cells, respectively) and to inhibit CDK1expression, which was reduced to 45% in Hs766T. Lastly, compound 6b passed the ADME prediction,showing good pharmacokinetic parameters. These data demonstrate that 6b displays cytotoxicactivity, induces apoptosis, and targets CDK1, supporting further studies for the development ofsimilar compounds against PDAC.