(19) Historically, the main paradigm in the development of kinase inhibitors was the development of selective inhibitors of specific kinases. (5,17в€’19) Multikinase inhibitors increase the survival time of patients with chronic myeloid leukemia and gastrointestinal stromal tumors for multiple years. They show increased effectiveness due to synergistic effects, decreased severe adverse effects compared to other anticancer drugs, and decreased development of resistance. The prime examples of multitarget agents in cancer therapy are multikinase inhibitors, such as imatinib, sunitinib, and sorafenib. (8в€’11) Furthermore, on the basis of the enhanced therapeutic effects of combination therapies, smaller therapeutic doses of the individual drugs are needed, which has the potential to decrease side effects compared to the individual drug treatments. Targeting two different pathways involved in the development of a disease often leads to additive or synergistic effects and can reduce the potential for the development of resistance. (7) To maximize their efficacy, the use of drug combinations has become a well-established approach. (6) Despite the many challenges of cancer therapies, current chemotherapeutics and targeted drugs can significantly prolong patient lives and in some cases also cure the disease.

(1в€’5) These diseases can be affected by many factors, and they are often resilient to single-target treatments due to activation of compensatory mechanisms and redundant cellular pathways. Multitarget therapies have for many years attracted the interest of medicinal chemists in the field of complex diseases, such as cancers, inflammation, psychiatric disorders, and thrombotic disorders. In this Perspective, we discuss the scientific background behind targeting topoisomerase II together with a number of other targets important in cancer therapy, review the present status, and discuss further options in the field. There are various different options for the preparation of dual-target or multiple-target inhibitors, as topoisomerase II is both structurally (e.g., topoisomerase I, Hsp90, and kinases) and functionally (e.g., histone deacetylases and proteasome) connected to many validated anticancer targets. To maximize the therapeutic potential of anticancer drugs, combination therapies and multitarget drugs have been suggested in many studies, where the use of multitarget drugs is advantageous from a pharmacokinetic point of view. Despite the clinical success of drugs that target topoisomerase II, the development of resistant cancer cells can limit their clinical efficacy. Human DNA topoisomerase II is an important target in anticancer therapy.

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