The design and discovery of topoisomerase-II inhibitors as new cancer drugs: current strategies and future perspectives.

Abstract

Introduction: Topoisomerases (Topo) are important targets in cancer chemotherapy due to their essential role in regulating DNA topology. Clinically used topoisomerase inhibitors, including poisons and catalytic inhibitors, produce anticancer effects by interfering with these processes. However, their long-term clinical use is often limited by drug resistance, cardiotoxicity, and myelosuppression, highlighting the need for safer and more effective alternatives.

Areas covered: This review evaluates Topo II inhibitors at various stages of clinical development. Literature published between January 2020 and January 2026 was collected from PubMed, Scopus, Embase, Web of Science, ClinicalTrials.gov, and Google Scholar using relevant keywords. The article highlights recent advances in the design, structural optimization, and biological evaluation of small-molecule Topo II inhibitors reported over the last five years. Particular emphasis is given to the development of catalytic inhibitors and multitarget agents aimed at overcoming limitations associated with conventional topoisomerase inhibitors.

Expert opinion: The transition from traditional Topo poisons to catalytic inhibitors and multitarget compounds represents a promising strategy to reduce toxicity and address resistance. Integrating medicinal chemistry, computational modeling, and preclinical pharmacology may facilitate the development of safer, more selective, and clinically translatable Topo II inhibitors for cancer therapy.