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Voreloxin is an anticancer quinolone derivative that intercalates DNA and poisons topoisomerase II
Rachael E Hawtin1, David E Stockett, Jo Ann W Byl
1Sunesis Pharmaceuticals, Inc., South San Francisco, California, United States of America. rhawtin@sunesis.com
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.
Methods/Principal Findings:
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/Significance:
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.
Insights
Voreloxin, a novel quinolone derivative, targets topoisomerase II (an enzyme crucial for DNA replication) to induce cancer cell death. This agent offers a new therapeutic avenue for patients resistant to existing topoisomerase II inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Topoisomerase II is a validated target for anti-cancer drugs like anthracyclines and epipodophyllotoxins.
- Existing drugs face limitations due to tumor resistance and side effects.
- Novel topoisomerase II agents are needed for resistant or intolerant cancer patients.
Purpose of the Study:
- To define the anticancer mechanism of action of voreloxin, a novel quinolone derivative.
- To understand voreloxin's molecular interactions and effects on topoisomerase II.
- To inform the rational clinical development of voreloxin.
Main Methods:
- Biochemical and cell-based assays were employed.
- DNA intercalation and topoisomerase II poisoning were assessed.
- Effects on DNA double-strand breaks, cell cycle arrest, and apoptosis were analyzed.
- Structure-activity relationships were explored using voreloxin analogs.
Main Results:
- Voreloxin intercalates DNA and inhibits topoisomerase II, leading to DNA damage, G2 arrest, and apoptosis.
- Voreloxin exhibits a distinct mechanism compared to existing topoisomerase II poisons.
- DNA intercalation was essential for voreloxin's anti-proliferative and G2 arrest activities.
Conclusions:
- Voreloxin is a first-in-class anticancer quinolone derivative targeting topoisomerase II with a unique mechanism.
- Understanding voreloxin's mechanism can guide the development of safer, more effective topoisomerase II-targeted cancer therapies.
- This research contributes to structure-activity relationship insights for novel anti-cancer drug design.
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