title: Voreloxin is an anticancer quinolone derivative that intercalates DNA and poisons topoisomerase II.
abstract: BACKGROUND
  Topoisomerase II is critical for DNA replication, transcription and chromosome segregation and is a well validated target of anti-neoplastic drugs including the anthracyclines and epipodophyllotoxins. However, these drugs are limited by common tumor resistance mechanisms and side-effect profiles. Novel topoisomerase II-targeting agents may benefit patients who prove resistant to currently available topoisomerase II-targeting drugs or encounter unacceptable toxicities. Voreloxin is an anticancer quinolone derivative, a chemical scaffold not used previously for cancer treatment. Voreloxin is completing Phase 2 clinical trials in acute myeloid leukemia and platinum-resistant ovarian cancer. This study defined voreloxin's anticancer mechanism of action as a critical component of rational clinical development informed by translational research.
  
  
  RESULTS
  Biochemical and cell-based studies established that voreloxin intercalates DNA and poisons topoisomerase II, causing DNA double-strand breaks, G2 arrest, and apoptosis. Voreloxin is differentiated both structurally and mechanistically from other topoisomerase II poisons currently in use as chemotherapeutics. In cell-based studies, voreloxin poisoned topoisomerase II and caused dose-dependent, site-selective DNA fragmentation analogous to that of quinolone antibacterials in prokaryotes; in contrast etoposide, the nonintercalating epipodophyllotoxin topoisomerase II poison, caused extensive DNA fragmentation. Etoposide's activity was highly dependent on topoisomerase II while voreloxin and the intercalating anthracycline topoisomerase II poison, doxorubicin, had comparable dependence on this enzyme for inducing G2 arrest. Mechanistic interrogation with voreloxin analogs revealed that intercalation is required for voreloxin's activity; a nonintercalating analog did not inhibit proliferation or induce G2 arrest, while an analog with enhanced intercalation was 9.5-fold more potent.
  
  
  CONCLUSIONS
  As a first-in-class anticancer quinolone derivative, voreloxin is a toposiomerase II-targeting agent with a unique mechanistic signature. A detailed understanding of voreloxin's molecular mechanism, in combination with its evolving clinical profile, may advance our understanding of structure-activity relationships to develop safer and more effective topoisomerase II-targeted therapies for the treatment of cancer.
authors.affiliation: Sunesis Pharmaceuticals, Inc., South San Francisco, California, United States of America. rhawtin@sunesis.com
authors.forename: Rachael E
authors.initials: RE
authors.lastname: Hawtin
authors.forename: David E
authors.initials: DE
authors.lastname: Stockett
authors.forename: Jo Ann W
authors.initials: JA
authors.lastname: Byl
authors.forename: Robert S
authors.initials: RS
authors.lastname: McDowell
authors.forename: Tan
authors.initials: T
authors.lastname: Nguyen
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Arkin
authors.forename: Andrew
authors.initials: A
authors.lastname: Conroy
authors.forename: Wenjin
authors.initials: W
authors.lastname: Yang
authors.forename: Neil
authors.initials: N
authors.lastname: Osheroff
authors.forename: Judith A
authors.initials: JA
authors.lastname: Fox
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D053938:DNA Fragmentation / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000187:drug effects*; D016503:Drug Delivery Systems; D005047:Etoposide / Q000494:pharmacology; D016195:G2 Phase; D006801:Humans; D007364:Intercalating Agents; D009287:Naphthyridines / Q000494:pharmacology* / Q000627:therapeutic use; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D007364:Intercalating Agents; D009287:Naphthyridines; D015363:Quinolones; D013844:Thiazoles; D005047:Etoposide; D004247:DNA; D004250:DNA Topoisomerases, Type II; C485113:vosaroxin