A new series of eighteen imidazo [2,1-b] [1,3,4]thiadiazole derivatives was efficiently synthesized andscreened for antiproliferative activity against the National Cancer Institute (NCI-60) cell lines panel. Twoout of eighteen derivatives, compounds 12a and 12h, showed remarkably cytotoxic activity with the halfmaximal inhibitory concentration values (IC50) ranging from 0.23 to 11.4 mM, and 0.29e12.2 mM,respectively. However, two additional compounds, 12b and 13g, displayed remarkable in vitro antiproliferativeactivity against pancreatic ductal adenocarcinoma (PDAC) cell lines, including immortalized(SUIT-2, Capan-1, Panc-1), primary (PDAC-3) and gemcitabine-resistant (Panc-1R), eliciting IC50 valuesranging from micromolar to sub-micromolar level, associated with significant reduction of cell-migrationand spheroid shrinkage. These remarkable results might be explained by modulation of key regulators ofepithelial-to-mesenchymal transition (EMT), including E-cadherin and vimentin, and inhibition ofmetalloproteinase-2/-9. High-throughput arrays revealed a significant inhibition of the phosphorylationof 45 tyrosine kinases substrates, whose visualization on Cytoscape highlighted PTK2/FAK as animportant hub. Inhibition of phosphorylation of PTK2/FAK was validated as one of the possible mechanismsof action, using a specific ELISA. In conclusion, novel imidazothiadiazoles show potent antiproliferativeactivity, mediated by modulation of EMT and PTK2/FAK.
- Drug Discovery
- Organic Chemistry