Topobexin targets the Topoisomerase II ATPase domain for beta isoform-selective inhibition and anthracycline cardioprotection

Jan Kubeš, Galina Karabanovich, Anh T. Q. Cong, Iuliia Melnikova, Olga Lenčová, Petra Kollárová, Hana Bavlovič Piskáčková, Veronika Keresteš, Lenka Applová, Lise C. M. Arrouye, Julia R. Alvey, Jasmina Paluncic, Taylor L. Witter, Anna Jirkovská, Jiří Kuneš, Petra Štěrbová-Kovaříková, Caroline A. Austin (), Martin Štěrba (), Tomáš Šimůnek (), Jaroslav Roh () and Matthew J. Schellenberg ()
Additional contact information
Jan Kubeš: Charles University; Hradec
Galina Karabanovich: Charles University; Hradec
Anh T. Q. Cong: Mayo Clinic
Iuliia Melnikova: Charles University; Hradec
Olga Lenčová: Charles University; Hradec
Petra Kollárová: Charles University; Hradec
Hana Bavlovič Piskáčková: Charles University; Hradec
Veronika Keresteš: Charles University; Hradec
Lenka Applová: Charles University; Hradec
Lise C. M. Arrouye: Mayo Clinic
Julia R. Alvey: Mayo Clinic
Jasmina Paluncic: Mayo Clinic
Taylor L. Witter: Mayo Clinic
Anna Jirkovská: Charles University; Hradec
Jiří Kuneš: Charles University; Hradec
Petra Štěrbová-Kovaříková: Charles University; Hradec
Caroline A. Austin: Newcastle University
Martin Štěrba: Charles University; Hradec
Tomáš Šimůnek: Charles University; Hradec
Jaroslav Roh: Charles University; Hradec
Matthew J. Schellenberg: Mayo Clinic

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-60167-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60167-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-60167-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().