Topoisomerase II-targeting anticancer clinical candidates and drugs: A critical analysis, unravelling molecular medicinal insights and promising research roadmap

Abstract

In recent years, the USFDA-approved drug molecules are being frequently analyzed to provide perspectives and strategies for novel therapeutic discovery and development. Some of the remarkable analyses include physicochemical properties of drugs relevant to oral bioavailability, frequent presence of drug relevant-structural motifs, natural products as sources of new drugs, and synthetic approaches to new drugs. In this review article, for the first time, we present a structure-function analysis of human topoisomerase II (hTopo II) inhibitors those are currently clinically used or under clinical trials for anticancer treatment. The case studies and a critical molecular medicinal insight for their therapeutic development have been presented. The review illustrates various key aspects: the hTopo II inhibitors' molecular modulations, common pharmacophores, interactions at molecular level crucial for inhibition of enzyme at its various stages of catalytic function, and network polypharmacology of Topo II with different targets. Numerous toxicophore motifs have been identified, which provide important alerts while designing and discovering novel therapeutic agents. A range of innovative approaches including property-focused strategies, ADCs, and Click Activated Protodrugs Against Cancer (CAPAC) that have addressed challenges faced in the hTopo II-based therapeutic development have been discussed. The analysis with perspectives represents a valuable educational and research resource that will encourage hTopo II-inhibition and its network polypharmacology based drug discovery studies.

Keywords: Drugs and clinical candidates; Polypharmacology; Property-focused approaches; Topoisomerase II; Toxicophores.