Topoisomerases as anticancer targets.

Area of Science:

• Biochemistry
• Pharmacology
• Oncology

Background:

• Precision medicine advances cancer treatment, but traditional anticancer agents remain vital for resistant or unresponsive cancers.
• DNA topoisomerases, particularly type IIA, are validated targets for anticancer and antibacterial drugs.
• Current topoisomerase poisons cause DNA damage but are linked to severe side effects like secondary cancers and cardiotoxicity.

Purpose of the Study:

• To review the role of topoisomerases as therapeutic targets in cancer treatment.
• To explore novel strategies for developing safer and more effective topoisomerase-targeting anticancer agents.
• To discuss the potential of designing isoform-specific inhibitors and catalytic inhibitors.

Main Methods:

• Review of existing literature on topoisomerase function, drug mechanisms, and structural biology.
• Analysis of structure-drug-DNA ternary complexes to understand poison binding sites.
• Exploration of recent advances in inhibitor design and discovery.

Main Results:

• Topoisomerase poisoning leads to replication fork arrest and DNA double-strand breaks, forming the basis of current drug action.
• Structural studies elucidate the precise mechanisms of topoisomerase poisons.
• Emerging strategies include designing isoform-specific human topoisomerase II poisons and catalytic inhibitors targeting inactive enzyme conformations.

Conclusions:

• Topoisomerases continue to be significant therapeutic targets for novel anticancer drug development.
• Developing isoform-specific inhibitors and catalytic inhibitors holds promise for safer and more effective cancer therapies.
• Insights from bacterial topoisomerase research may inspire new human topoisomerase inhibitor discovery.