Discovery of Diaryl Piperidone-Sulfonamide as a Novel Dual-Target Inhibitor of STAT3/CAIX Inducing Ferroptosis in Triple-Negative Breast Cancer Cells.

A series of diaryl piperidone-sulfonamide derivatives were designed as dual inhibitors of STAT3/CAIX and ferroptosis inducers for triple-negative breast cancer (TNBC). The representative compound 7m demonstrated significant antitumor effects against the MDA-MB-231 cell line both in vitro and in vivo. Mechanistically, 7m inhibits the phosphorylation of STAT3, with a binding affinity determined by surface plasmon resonance (SPR) analysis (KD = 60.03 ± 8.13 μM). Additionally, 7m exhibits potent inhibitory activity against CA IX (IC50 = 80.45 ± 39.7 nM) and shows enhanced antitumor activity under hypoxic conditions compared to normoxic conditions. Molecular docking studies suggest a rational binding mode between 7m and the SH2 domain of STAT3, as well as with the CA IX protein. Furthermore, 7m increases the levels of reactive oxygen species (ROS) and lipid peroxides in MDA-MB-231 cells, thereby inducing ferroptosis. These findings provide a novel therapeutic strategy for the treatment of TNBC.