Prestigious journal Nature Communications publishes results from the CardioTox Hradec Králové team
Anthracycline antibiotics, such as doxorubicin and daunorubicin, are among the most important anticancer chemotherapeutics. However, their use is limited by serious toxic effects on the heart. Anthracyclines damage cardiomyocytes through the enzyme topoisomerase II beta (TOP2B), which can ultimately lead to heart failure. The only cardioprotective agent currently used in clinical practice is dexrazoxane, but it is non-selective and also inhibits the alpha isoform of this enzyme (TOP2A), which is present in tumor cells. This raises concerns about a potential reduction in the anticancer efficacy of anthracyclines and significantly limits the broader application of cardioprotection in clinical settings. Although topoisomerase II has been a subject of intensive research since its discovery in the 1970s, no selective TOP2B inhibitor suitable for this pharmacological use has been known—until now.
The international scientific team working under the name CardioTox Hradec Králové previously made significant contributions to elucidating the cardioprotective mechanism of dexrazoxane and identified the beta isoform of topoisomerase II (TOP2B) as a key target for cardioprotective intervention. In collaboration with the Mayo Clinic (USA) and Newcastle University (UK), the team has now published a groundbreaking discovery of the first selective TOP2B inhibitor, named topobexin. This novel compound targets a previously unrecognized binding site in the ATPase domain of the enzyme and, as the first compound of its kind, selectively inhibits TOP2B via a unique mechanism. As a result, it retains the ability to protect the myocardium without interfering with the anticancer effects of chemotherapy.
Topobexin demonstrated strong cardioprotective efficacy in vitro on primary cardiomyocytes and in vivo in a rabbit model of chronic anthracycline-induced cardiotoxicity, where it effectively prevented both structural and functional changes in the myocardium caused by anthracyclines.
This discovery was significantly aided by rational drug design based on structural crystallographic analysis of a novel binding site that differs between TOP2A and TOP2B. The breakthrough not only paves the way for the development of safer cardioprotective agents, but also opens new avenues for detailed studies into the biological roles of individual topoisomerase II isoforms.
The discovery was also highlighted by Scienmag, which published a short review of the breakthrough.
The study was conducted by research teams led by Assoc. Prof. Jaroslav Roh, Prof. Tomáš Šimůnek, and Assoc. Prof. Petra Štěrbová (Faculty of Pharmacy in Hradec Králové, Charles University), Assoc. Prof. Martin Štěrba (Faculty of Medicine in Hradec Králové, Charles University), Dr. Matthew Schellenberg (Mayo Clinic), and Prof. Caroline Austin (Newcastle University). The first author of the study is Jan Kubeš, a PhD student in the doctoral program "Xenobiochemistry and Pathobiochemistry" at the Faculty of Pharmacy, Charles University.
Text: CardioTox Hradec Králové team
Intellectual property associated with this discovery and its translational potential is protected by a joint international patent of both Charles University faculties and the Mayo Clinic (PCT/US2024/043047, Topoisomerase IIB Inhibitors).
The research was supported by the NETPHARM project (reg. no. CZ.02.01.01/00/22_008/0004607), co-funded by the European Union, the INTER-EXCELLENCE II project of the Ministry of Education, Youth and Sports of the Czech Republic (reg. no. LUAUS24335) and the Grant Agency of the Czech Republic (reg. no. 23-06558S).
