The prestigious journal Nature Communications has published unique research results from the CardioTox Hradec Králové team. Anthracycline antibiotics, such as doxorubicin or daunorubicin, are among the key anti-cancer chemotherapeutics, but their use is limited by severe toxic effects on the heart. Anthracyclines damage cardiomyocytes via the enzyme topoisomerase II beta (TOP2B), which can lead to heart failure. So far, the only clinically used cardioprotective agent is dexrazoxane, but it is not selective and also inhibits the alpha isoform of this enzyme (TOP2A), which is present in cancer cells. This raises concerns about the attenuation of the antitumour effect of anthracyclines and substantially reduces the use of cardioprotection in clinical practice. Although the TOP2 enzyme has been the subject of intense research since its discovery in the 1970s, no TOP2B selective inhibitor suitable for this pharmacological application has been known.
The international scientific team associated under the brand CardioTox Hradec Králové has contributed substantially to the elucidation of the mechanism of the cardioprotective effect of dexrazoxane and defined TOP2B as a key target for cardioprotective intervention. Now, this collective has teamed up with the US Mayo Clinic and the UK's Newcastle University to publish the breakthrough discovery of the first selective TOP2B inhibitor, called topobexin. "This targets an entirely new binding site in the ATPase domain of the enzyme and is the first compound of its kind to preferentially inhibit TOP2B activity through an original mechanism. Thanks to this, it retains the ability to protect the myocardium without interfering with the anti-tumour effect of anthracycline chemotherapy," explains Associate Professor Martin Štěrba, head of the research group at the Faculty of Medicine in Hradec Králové.
Topobexin demonstrated significant cardioprotective efficacy in vitro in primary cardiomyocytes and in vivo in a rabbit model of chronic anthracycline cardiotoxicity, where it effectively prevented both structural and functional myocardial changes induced by anthracycline.
A rational design of the candidate drug based on structural crystallographic analysis of a novel binding site that differs between TOP2A and TOP2B contributed substantially to this discovery. This discovery paves the way not only for the development of safer cardioprotective drugs, but also for the detailed study of the biological role of individual TOP2 isoforms.
The discovery was noticed by Scienmag magazine, which published a short article about it.
This success is proof that top scientific discoveries are also being made in the Czech Republic, and it is no coincidence that it is the result of the NETPHARM project supported by the the Ministry of Education, Youth and Sports "Top Research Challenge".
The study was carried out by the research team of Assoc. Prof. Martin Štěrba (co-authors are Dr. Olga Lenčová and Dr. Petra Kollárová). The multidisciplinary collaboration also involved three teams from Charles University, the Faculty of Pharmacy in Hradec Králové (led by Assoc. Prof. Jaroslav Roh, Prof. Tomáš Šimůnek and Assoc. Prof. Petra Štěrbová) and the team of Dr. Matthew Schellenberg from Mayo Clinic (USA) and Prof. Caroline Austin from Newcastle University (UK).
The intellectual property related to the discovery and its application potential towards practice is protected by a joint international patent of both faculties of Charles University and 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).
Faculty of Medicine in Hradec Králové
Charles University
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