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Lookup NU author(s): Professor Caroline AustinORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025.Topoisomerase II alpha and beta (TOP2A and TOP2B) isoenzymes perform essential and non-redundant cellular functions. Anthracyclines induce their potent anti-cancer effects primarily via TOP2A, but at the same time they induce a dose limiting cardiotoxicity through TOP2B. Here we describe the development of the obex class of TOP2 inhibitors that bind to a previously unidentified druggable pocket in the TOP2 ATPase domain to act as allosteric catalytic inhibitors by locking the ATPase domain conformation with the capability of isoform-selective inhibition. Through rational drug design we have developed topobexin, which interacts with residues that differ between TOP2A and TOP2B to provide inhibition that is both selective for TOP2B and superior to dexrazoxane. Topobexin is a potent protectant against chronic anthracycline cardiotoxicity in an animal model. This demonstration of TOP2 isoform-specific inhibition underscores the broader potential to improve drug specificity and minimize adverse effects in various medical treatments.
Author(s): Kubes J, Karabanovich G, Cong ATQ, Melnikova I, Lencova O, Kollarova P, Bavlovic Piskackova H, Kerestes V, Applova L, Arrouye LCM, Alvey JR, Paluncic J, Witter TL, Jirkovska A, Kunes J, Sterbova-Kovarikova P, Austin CA, Sterba M, Simunek T, Roh J, Schellenberg MJ
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2025
Volume: 16
Issue: 1
Online publication date: 28/05/2025
Acceptance date: 14/05/2025
Date deposited: 10/06/2025
ISSN (electronic): 2041-1723
Publisher: Nature Research
URL: https://doi.org/10.1038/s41467-025-60167-9
DOI: 10.1038/s41467-025-60167-9
Data Access Statement: Plasmids used in this study are available upon request from the cor- responding authors. Atomic coordinates and structure factors have been deposited in the PDB under accession numbers 9BQ6 (TOP2A ATPase), 9BQ7 (TOP2A ATPase + BNS-22), 9BQ9 (TOP2A ATPase + obex 5c), 9BQB (TOP2A ATPase + topobexin), 9BQ8 (TOP2B ATPase), 9BQA (TOP2B ATPase + BNS-22), 9BQC (TOP2B ATPase + obex 5c), and 9BQD (TOP2B ATPase + topobexin). The X-ray crystallographic coor- dinates for small molecule structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers 2354347 (topobexin (9)) and 2354203 (BNS-22). These data can be obtained free of charge from The Cam- bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_ request/cif. Supplementary information is available for this paper. Source data are provided with this paper.
PubMed id: 40425539
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