First-In-Class\nThiosemicarbazone Metal Complexes Targeting\nthe Sigma‑2 Receptor (S2R) as an Innovative Strategy against\nPancreatic Cancer

Pancreatic cancer, with its increasing\nincidence and lowest 5-year\nsurvival rate, is predicted to become the second leading cause of\ncancer deaths by 2030. Current clinical trials have shown limited\nimprovement, highlighting the need for new therapies. The sigma-2\nreceptor (S2R), with roles in tumor progression, is a target for novel\nthiosemicarbazones (TSCs). <b>FA4</b> has shown potent activity\nagainst pancreatic cancer <i>in vivo</i>. We synthesized\ncomplexes of <b>FA4</b> with Cu(II) and Pt(II), and compared\ntheir efficacy with complexes of the non-S2R-targeting TSC <b>1</b>. TSC-Cu exhibited over 50-fold higher <i>in vitro</i> cytotoxicity\nthan TSCs-Pt, which was less active than TSCs. <b>FA4</b>-Cu\ninduced apoptotic cell death <i>via</i> ER and mitochondrial\nstress showing more potent activity than <b>FA4</b>. This <i>in vitro</i> effect was replicated in the preclinical PANC-1\nmodel, where <b>FA4</b>-Cu was more potent than <b>FA4</b>, <b>1</b>, and <b>1</b>-Cu. These results support further\nexploration of <b>FA4</b>-Cu as a potential therapy for pancreatic\ncancer.