Acharya Ayan, Roy Nibedita, Newaskar Vaishnavi, Rai Abhishek, Ghosh Abhrajyoti, Nagpure Mithilesh, Giri Santosh Kumar, Sahni Gautam, Guchhait Sankar K
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar, Mohali, Punjab, 160062, India.
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar, Mohali, Punjab, 160062, India.
Eur J Med Chem. 2025 Jul 5;291:117611. doi: 10.1016/j.ejmech.2025.117611. Epub 2025 Apr 11.
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.
近年来，人们经常对美国食品药品监督管理局（USFDA）批准的药物分子进行分析，以提供新疗法发现与开发的观点和策略。其中一些显著的分析包括与口服生物利用度相关的药物物理化学性质、药物相关结构基序的频繁出现、作为新药来源的天然产物以及新药的合成方法。在这篇综述文章中，我们首次对目前临床上用于抗癌治疗或正在进行临床试验的人类拓扑异构酶II（hTopo II）抑制剂进行了结构-功能分析。文中呈现了案例研究以及对其治疗开发的关键分子医学见解。该综述阐述了各个关键方面：hTopo II抑制剂的分子调节、常见药效基团、在分子水平上对酶催化功能不同阶段抑制至关重要的相互作用，以及Topo II与不同靶点的网络多药理学。已鉴定出众多毒性基团基序，这在设计和发现新型治疗药物时提供了重要警示。文中还讨论了一系列创新方法，包括以性质为重点的策略、抗体药物偶联物（ADCs）以及点击激活抗癌前药（CAPAC），这些方法解决了基于hTopo II的治疗开发中面临的挑战。从不同角度进行的分析是一种宝贵的教育和研究资源，将推动基于hTopo II抑制及其网络多药理学的药物发现研究。
