Identification of a Small-Molecule Inhibitor of DNA Topoisomerase II by Proteomic Profiling

SummaryBNS-22, a chemically synthesized derivative of the natural plant product GUT-70, has antiproliferative activity against human cancer cells, the mechanism of which is unknown. Here, we identify a target of BNS-22 by proteomic profiling analysis, which suggests that BNS-22 belongs to the same cluster as ICRF-193, a DNA topoisomerase II (TOP2) catalytic inhibitor. BNS-22 inhibits kinetoplast DNA decatenation that is mediated by human TOP2α and TOP2β in vitro at an IC50 of 2.8 and 0.42 μM, respectively. BNS-22 does not affect DNA damage and antagonizes TOP2 poison-mediated DNA damage. Like ICRF-193, BNS-22 induces mitotic abnormalities, characterized by impairments in chromosome alignment and segregation, thereby causing polyploidy in HeLa cells. These results indicate that BNS-22 targets TOP2 and acts as its catalytic inhibitor.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (265 K)Download as PowerPoint slideHighlights► Target prediction of a small molecule by proteomic profiling ► BNS-22 targets TOP2 and acts as its catalytic inhibitor ► A new TOP2 inhibitor is a promising agent for the development of an anticancer drug