Topobexin targets the Topoisomerase II ATPase domain for beta isoform-selective inhibition and anthracycline cardioprotection
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| Language: | English |
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2025
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| _version_ | 1866901868017352704 |
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| author | Kubeš, Jan Karabanovich, Galina Cong, Anh T. Q. Melnikova, Iuliia Lenčová, Olga Kollárová, Petra Bavlovič Piskáčková, Hana Keresteš, Veronika Applova, Lenka Arrouye, Lise C. M. Alvey, Julia Paluncic, Jasmina Witter, Taylor Jirkovská, Anna Kuneš, Jiří Sterbova, Petra Austin, Caroline Štěrba, Martin Simunek, Tomas Roh, Jaroslav Schellenberg, Matthew |
| author_facet | Kubeš, Jan Karabanovich, Galina Cong, Anh T. Q. Melnikova, Iuliia Lenčová, Olga Kollárová, Petra Bavlovič Piskáčková, Hana Keresteš, Veronika Applova, Lenka Arrouye, Lise C. M. Alvey, Julia Paluncic, Jasmina Witter, Taylor Jirkovská, Anna Kuneš, Jiří Sterbova, Petra Austin, Caroline Štěrba, Martin Simunek, Tomas Roh, Jaroslav Schellenberg, Matthew |
| contents | <p>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 <em>obex</em> 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.</p> |
| format | Recurso digital |
| id | zenodo_https___doi_org_10_5281_zenodo_15535039 |
| institution | Zenodo |
| language | eng |
| publishDate | 2025 |
| publisher | Zenodo |
| record_format | zenodo |
| spellingShingle | Topobexin targets the Topoisomerase II ATPase domain for beta isoform-selective inhibition and anthracycline cardioprotection Kubeš, Jan Karabanovich, Galina Cong, Anh T. Q. Melnikova, Iuliia Lenčová, Olga Kollárová, Petra Bavlovič Piskáčková, Hana Keresteš, Veronika Applova, Lenka Arrouye, Lise C. M. Alvey, Julia Paluncic, Jasmina Witter, Taylor Jirkovská, Anna Kuneš, Jiří Sterbova, Petra Austin, Caroline Štěrba, Martin Simunek, Tomas Roh, Jaroslav Schellenberg, Matthew cardiovascular biology enzyme mechanisms medicinal chemistry Crystallography, X-Ray <p>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 <em>obex</em> 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.</p> |
| title | Topobexin targets the Topoisomerase II ATPase domain for beta isoform-selective inhibition and anthracycline cardioprotection |
| topic | cardiovascular biology enzyme mechanisms medicinal chemistry Crystallography, X-Ray |
| url | https://doi.org/10.5281/zenodo.15535039 |