6533b839fe1ef96bd12a5ae0
RESEARCH PRODUCT
Imidazo[2,1-b] [1,3,4]thiadiazoles with antiproliferative activity against primary and gemcitabine-resistant pancreatic cancer cells
Stella CascioferroBarbara ParrinoElisa GiovannettiGodefridus J. PetersDaan P. GeerkeNiccola FunelCecilia BergonziniGiulia MantiniHenk L. DekkerGiovanna Li PetriPatrizia DianaGirolamo CirrincioneDaniela Carbonesubject
Inhibition of migrationAntimetabolites AntineoplasticEpithelial-Mesenchymal Transition3Modulation of EMTPTK2VimentinAntineoplastic AgentsApoptosisThiophenesAntiproliferative activity1-b][1DeoxycytidinePancreatic ductal adenocarcinomaThiadiazolesSDG 3 - Good Health and Well-beingCell MovementPancreatic cancerDrug DiscoveryThiadiazolesmedicineTumor Cells CulturedImidazo[21-b][134]thiadiazole derivativesHumansPTK2/FAKIC50Cell ProliferationImidazo[2Pharmacologybiology4]thiadiazole derivativesChemistryOrganic ChemistryDrug SynergismGeneral Medicinemedicine.diseaseGemcitabinePancreatic NeoplasmsCell cultureDrug Resistance NeoplasmImidazo[21-b][134]thiadiazole derivatives Pancreatic ductal adenocarcinoma Antiproliferative activity Inhibition of migration Spheroids shrinkage Modulation of EMT PTK2/FAKbiology.proteinCancer research/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_beingPhosphorylationSpheroids shrinkageTyrosine kinaseCarcinoma Pancreatic Ductaldescription
A new series of eighteen imidazo [2,1-b] [1,3,4]thiadiazole derivatives was efficiently synthesized and screened for antiproliferative activity against the National Cancer Institute (NCI-60) cell lines panel. Two out of eighteen derivatives, compounds 12a and 12h, showed remarkably cytotoxic activity with the half maximal inhibitory concentration values (IC50) ranging from 0.23 to 11.4 μM, and 0.29–12.2 μM, respectively. However, two additional compounds, 12b and 13g, displayed remarkable in vitro antiproliferative activity 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 values ranging from micromolar to sub-micromolar level, associated with significant reduction of cell-migration and spheroid shrinkage. These remarkable results might be explained by modulation of key regulators of epithelial-to-mesenchymal transition (EMT), including E-cadherin and vimentin, and inhibition of metalloproteinase-2/-9. High-throughput arrays revealed a significant inhibition of the phosphorylation of 45 tyrosine kinases substrates, whose visualization on Cytoscape highlighted PTK2/FAK as an important hub. Inhibition of phosphorylation of PTK2/FAK was validated as one of the possible mechanisms of action, using a specific ELISA. In conclusion, novel imidazothiadiazoles show potent antiproliferative activity, mediated by modulation of EMT and PTK2/FAK.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2020-03-01 | European Journal of Medicinal Chemistry |