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.

Biosciences Institute Newcastle University Newcastle upon Tyne NE1 7RU UK

Department of Biochemical Sciences Faculty of Pharmacy in Hradec Králové Charles University; Hradec Králové 500 03 Czech Republic

Department of Biochemistry and Molecular Biology Mayo Clinic Rochester 55905 MN USA

Department of Organic and Bioorganic Chemistry Faculty of Pharmacy in Hradec Králové Charles University; Hradec Králové 500 03 Czech Republic

Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Faculty of Pharmacy in Hradec Králové Charles University; Hradec Králové 500 03 Czech Republic

Department of Pharmacology Faculty of Medicine in Hradec Králové Charles University; Hradec Králové 500 03 Czech Republic

Mayo Clinic Graduate School of Biomedical Sciences Mayo Clinic Rochester 55905 MN USA

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