First-In-Class Thiosemicarbazone Metal Complexes Targeting the Sigma-2 Receptor (S2R) as an Innovative Strategy against Pancreatic Cancer.

Pancreatic cancer, with its increasing incidence and lowest 5-year survival rate, is predicted to become the second leading cause of cancer deaths by 2030. Current clinical trials have shown limited improvement, highlighting the need for new therapies. The sigma-2 receptor (S2R), with roles in tumor progression, is a target for novel thiosemicarbazones (TSCs). has shown potent activity against pancreatic cancer . We synthesized complexes of with Cu(II) and Pt(II), and compared their efficacy with complexes of the non-S2R-targeting TSC . TSC-Cu exhibited over 50-fold higher cytotoxicity than TSCs-Pt, which was less active than TSCs. -Cu induced apoptotic cell death ER and mitochondrial stress showing more potent activity than . This effect was replicated in the preclinical PANC-1 model, where -Cu was more potent than , , and -Cu. These results support further exploration of -Cu as a potential therapy for pancreatic cancer.