Human Topoisomerase I Inhibitors

Abstract

Topoisomerases are ubiquitous enzymes that solve topological problems due to DNA (deoxyribonucleic acid) supercoiling occurring during the replication, transcription, recombination and chromatin remodelling processes. Human topoisomerase IB (Topo IB) is the selective target of camptothecin, a natural compound from which two powerful anticancer drugs, topotecan and irinotecan, are produced. Camptothecin acts as an interfacial inhibitor interacting with both the enzyme and DNA stabilising the covalent enzyme–DNA complex, and slowing down the religation of the broken DNA strands brings cells to death. Topo IB is also important for transcription of genes involved in neurodevelopment, and its inhibition during critical stages of brain development may be responsible for neurodevelopmental disorders. Key Concepts Topoisomerases are crucial enzymes essential in the relaxation of supercoiled DNA. Human topoisomerase IB cuts a single DNA strand forming a transient enzyme–DNA cleavage complex. Camptothecin is a natural compound of which human topoisomerase IB is the only cellular target. Camptothecin can trap the enzyme–DNA cleavage complex bringing cells to death. Two camptothecin derivatives have been approved by the US Food and Drug Administration: topotecan for ovarian and lung cancers and irinotecan for colorectal cancer. Camptothecin and its derivatives act as interfacial inhibitors interacting with both the enzyme and the DNA. Single topoisomerase mutation may induce resistance to camptothecin. New non‐camptothecin derivatives are under development. The cytotoxic activity of camptothecin increases in the presence of other compounds inhibiting enzymes involved in DNA repair. Inhibition of topoisomerase IB has also a strong influence on the modulation expression of groups of genes associated with autism.