Voreloxin Is an Anticancer Quinolone Derivative that Intercalates DNA and Poisons Topoisomerase II

摘要: Background Topoisomerase II is critical for DNA replication, transcription and chromosome segregation a well validated target of anti-neoplastic drugs including the anthracyclines epipodophyllotoxins. However, these are limited by common tumor resistance mechanisms side-effect profiles. Novel topoisomerase II-targeting agents may benefit patients who prove resistant to currently available or encounter unacceptable toxicities. Voreloxin an anticancer quinolone derivative, chemical scaffold not used previously cancer treatment. completing Phase 2 clinical trials in acute myeloid leukemia platinum-resistant ovarian cancer. This study defined voreloxin's mechanism action as component rational development informed translational research. Methods/Principal Findings Biochemical cell-based studies established that voreloxin intercalates poisons II, causing double-strand breaks, G2 arrest, apoptosis. differentiated both structurally mechanistically from other use chemotherapeutics. In studies, poisoned caused dose-dependent, site-selective fragmentation analogous antibacterials prokaryotes; contrast etoposide, nonintercalating epipodophyllotoxin poison, extensive fragmentation. Etoposide's activity was highly dependent on while intercalating anthracycline doxorubicin, had comparable dependence this enzyme inducing arrest. Mechanistic interrogation with analogs revealed intercalation required activity; analog did inhibit proliferation induce enhanced 9.5-fold more potent. Conclusions/Significance As first-in-class toposiomerase agent unique mechanistic signature. A detailed understanding molecular mechanism, combination its evolving profile, advance our structure-activity relationships develop safer effective II-targeted therapies treatment