Topoisomerase I inhibitors: Challenges, progress and the road ahead

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• Topoisomerase IB (Top1) is upregulated in numerous tumor cells, making it a critical target for anticancer drug development.
• Current FDA-approved Top1 inhibitors, like camptothecin (CPT) derivatives, stabilize the DNA-Top1-drug complex but have limitations.

Purpose of the Study:

• To chronologically review the development of Top1 poisons from natural and synthetic origins.
• To analyze structure-activity relationships (SAR) and identify key structural features for Top1 inhibition.
• To provide insights into the structural basis of Top1 inhibition and its application in combination therapies.

Main Methods:

• Literature review of Top1 poisons, focusing on chronological development.
• Structure-activity relationship (SAR) analysis of different chemotypes.
• Examination of structural basis for Top1 inhibition.

Main Results:

• Identification of various classes of Top1 poisons with distinct structural features contributing to inhibition.
• Understanding of SAR for different Top1 inhibitor chemotypes.
• Overview of Top1 poisons' application in contemporary combination therapies.

Conclusions:

• The development of non-camptothecin Top1 poisons is crucial due to limitations of existing drugs.
• SAR analysis provides valuable insights for designing novel and effective Top1 inhibitors.
• Top1 poisons hold promise for future anticancer strategies, particularly in combination therapies.