Barettin Suppresses Pancreatic Ductal Adenocarcinoma Proliferation via Topoisomerase IIα Inhibition.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with few therapeutic options. Topoisomerase IIα (TOPO2α) is frequently overexpressed in PDAC and is associated with poor clinical outcomes, yet current TOPO2α-directed therapies are constrained by limited efficacy and toxicity. Barettin, a brominated indole-containing diketopiperazine isolated from the marine sponge Geodia barretti, has not previously been evaluated against PDAC-relevant targets. Here, we identify barettin as a TOPO2α inhibitor using an integrated phenotypic, computational, and biochemical approach. Barettin exerts a cytostatic, non-toxic effect, selectively suppressing proliferation in a subset of PDAC models while showing reduced activity in others, revealing context-dependent efficacy and biological selectivity. Consistent with this, barettin inhibits TOPO2α-mediated DNA decatenation in vitro, demonstrating direct interference with enzyme activity. These findings support barettin as a selective inhibitor of a cancer-relevant proliferative pathway, uncovering a potential vulnerability in a subset of PDAC.