The design and discovery of topoisomerase I inhibitors as anticancer therapies

Introduction Cancer has been identified as one of the leading causes of death worldwide. The biological target of some anticancer agents is topoisomerase I, an enzyme involved in the relaxation of supercoiled DNA. The synthesis of new compounds with antiproliferative effect and behaving as topoisomerase I inhibitors has become an active field of research. Depending on their mechanism of inhibition, they can be classified as catalytic inhibitors or poisons. Areas covered This review article summarizes the state of the art for the development of selective topoisomerase I inhibitors. Collected compounds showed inhibition of the enzyme, highlighting those approved for clinical use, the combination therapies developed, as well as related drawbacks and future focus. Expert opinion Research related to topoisomerase I inhibitors in cancer therapy started with camptothecin (CPT). This compound was first selected as a good anticancer agent and then topoisomerase I was identified as its therapeutic target. Derivatives of CPT irinotecan, topotecan, and belotecan are the only clinically approved inhibitors. Currently, their limitations are being addressed by different stretegies. Future studies should focus not only on developing other active molecules but also on improving the bioavailability and pharmacokinetics of potent synthetic derivatives.

Automated summary

This review article provides an overview of the development of selective topoisomerase I inhibitors for cancer therapy, focusing on approved compounds, combination therapies, drawbacks, and future research directions. Studies on improving bioavailability and pharmacokinetics of potent synthetic derivatives are important for addressing the limitations of current clinically approved inhibitors.