Activity of Fluoro-Substituted 3,5-Di[(E)-Benzylidene]piperidin-4-Ones with N-Arylsulfonyl Appendages Against KRAS-Mutant Pancreatic Ductal Adenocarcinoma Cells

KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a high mortality that still lacks efficient therapies. Monoketone-based bisarylidene curcuminoid derivatives have shown promising activities against various PDAC models. Based on our previous findings on anticancer-active N-acryloyl-modified piperidin-4-one derivatives, we replaced the reactive acryloyl moiety by a series of N-arylsulfonyl bis-difluoro/trifluoromethylbenzylidene piperidin-4-one derivatives and tested them for antiproliferative activity against KRAS-mutant PDAC cells. Furthermore, apoptosis induction based on caspase-3/7 activation and STAT3 inhibition were investigated for the most promising compound. Notably, the N-tosyl derivative 3a with 4-trifluoromethyl substituents at the benzylidene rings exhibited the highest antiproliferative activities against PDAC cells (IC50 = 0.22–0.26 µM, 48 h). Derivative 3a also strongly induced apoptosis in PDAC cells and suppressed STAT3 activation/phosphorylation, which was supported by molecular docking of this curcuminoid into the SH2 domain of STAT3 and by 3a-STAT3 binding confirmed using CETSA in MiaPaCa-2 cells. These findings identify compound 3a as a promising lead for further preclinical evaluation in KRAS-mutant PDAC models and in other STAT3-dependent cancer types.