First dual inhibitors of human topoisomerase IIα and Hsp90 C-terminal domain inhibit the growth of Ewing sarcoma in vitro and in vivo

Dernovšek, Jaka (author), Urbančič, Dunja (author), Zajec, Živa (author), Skok, Žiga (author), Ilaš, Janez (author), Zidar, Nace (author), Tomašič, Tihomir (author)

Heat shock protein 90 (Hsp90) and topoisomerase IIα (TopoIIα) are members of the GHKL protein superfamily, both with clinically validated roles as anticancer drug targets. We report the discovery of the first class of dual inhibitors targeting the ATP-binding site of TopoIIα and the C-terminal domain of Hsp90, displaying potent cancer growth inhibition both in vitro and in vivo. Initially, a known TopoIIα inhibitor, compound 3, was shown to bind to the C-terminal domain of Hsp90, but not to its ATP-binding N-terminal domain. Nineteen analogs were then prepared and evaluated to investigate the structure–activity relationships, several of which inhibited the growth of SK-N-MC Ewing sarcoma cells in vitro. Compound 3 emerged as one of the most potent growth inhibitors (IC$_{50}$ = 0.33 ± 0.04 µM), demonstrating the ability to induce apoptosis and cell cycle arrest in SK-N-MC cells in vitro, and to slow the growth of Ewing sarcoma in vivo in a zebrafish model.

• Language: English
• Keywords: cancer, Ewing sarcoma, Hsp90, inhibitor, topoisomerase IIα, zebrafish
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: 20 str.
• Numbering: Vol. 153, art. 107850
• PID: 20.500.12556/RUL-163948
• UDC: 616-006
• ISSN on article: 0045-2068
• DOI: 10.1016/j.bioorg.2024.107850
• COBISS.SI-ID: 209903875
• Publication date in RUL: 14.10.2024

DERNOVŠEK, Jaka, URBANČIČ, Dunja, ZAJEC, Živa, SKOK, Žiga, ILAŠ, Janez, ZIDAR, Nace and TOMAŠIČ, Tihomir, 2024, First dual inhibitors of human topoisomerase IIα and Hsp90 C-terminal domain inhibit the growth of Ewing sarcoma in vitro and in vivo. Bioorganic chemistry [online]. 2024. Vol. 153, no. 107850. [Accessed 13 April 2025]. DOI 10.1016/j.bioorg.2024.107850. Retrieved from: https://repozitorij.uni-lj.si/IzpisGradiva.php?lang=eng&id=163948

Record is a part of a journal

• Title: Bioorganic chemistry
• Shortened title: Bioorg. chem.
• Publisher: Elsevier
• ISSN: 0045-2068
• COBISS.SI-ID: 25099008

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: rak, medicina, sarkom