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 (avtor), Urbančič, Dunja (avtor), Zajec, Živa (avtor), Skok, Žiga (avtor), Ilaš, Janez (avtor), Zidar, Nace (avtor), Tomašič, Tihomir (avtor)

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.

• Jezik: Angleški jezik
• Ključne besede: cancer, Ewing sarcoma, Hsp90, inhibitor, topoisomerase IIα, zebrafish
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2024
• Št. strani: 20 str.
• Številčenje: Vol. 153, art. 107850
• PID: 20.500.12556/RUL-163948
• UDK: 616-006
• ISSN pri članku: 0045-2068
• DOI: 10.1016/j.bioorg.2024.107850
• COBISS.SI-ID: 209903875
• Datum objave v RUL: 14.10.2024

Gradivo je del revije

• Naslov: Bioorganic chemistry
• Skrajšan naslov: Bioorg. chem.
• Založnik: Elsevier
• ISSN: 0045-2068
• COBISS.SI-ID: 25099008

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: rak, medicina, sarkom