Investigational DNA topoisomerase I inhibitors for colorectal cancer: preclinical and early phase developments.

Colorectal cancer, a significant global challenge, requires innovative treatment strategies. DNA topoisomerase I inhibitors, which disrupt DNA replication in rapidly proliferating cancer cells, have shown great potential. Natural product derivatives, such as camptothecin (CPT), and emerging compounds for CRC treatment have made significant progress. This review article summarizes the state of the art in the development of selective topoisomerase I inhibitors, which show in vitro and in vivo activity against colorectal cancer in preclinical and early stage clinical trials. The compounds are classified into natural compounds and derivatives and new synthetic compounds classified according to their cyclic structure. Despite the success of CPT derivatives like irinotecan, topotecan and belotecan (approved drugs), drawbacks such as lactone instability have led to the development of modified compounds. Structural modifications in CPT derivatives, like derived homocamptothecins, show enhanced efficacy and reduced toxicity. Additionally, synthetic compounds like indenoisoquinolines and quinolines have emerged as potent TOP1 inhibitors. Dual inhibitors, combination therapies, integration with immunotherapy and personalized medicine further enhances treatment efficacy. Ongoing preclinical studies offer hope for improved CRC management.