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

• Published in: Bioorganic chemistry 2024-12, Vol.153, p.107850, Article 107850
• Main Authors: Dernovšek, Jaka, Urbančič, Dunja, Zajec, Živa, Sturtzel, Caterina, Grissenberger, Sarah, Wenninger-Weinzierl, Andrea, Gedgaudas, Marius, Zubrienė, Asta, Goričan, Tjaša, Golič Grdadolnik, Simona, Skok, Žiga, Ilaš, Janez, Distel, Martin, Zidar, Nace, Tomašič, Tihomir
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Neoplasm - metabolism; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; DNA Topoisomerases, Type II - metabolism; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - metabolism; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Ewing sarcoma; Hsp90; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - metabolism; Humans; Inhibitor; Molecular Structure; Sarcoma, Ewing - drug therapy; Sarcoma, Ewing - metabolism; Sarcoma, Ewing - pathology; Structure-Activity Relationship; Topoisomerase II Inhibitors - chemical synthesis; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology; Topoisomerase IIα; Zebrafish
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107850

[Display omitted] •Discovery of dual inhibitors of Hsp90 CTD and TopoIIα ATP-binding site.•Structure-activity relationships investigated with 19 analogs.•Compound 3 targets Hsp90 CTD, not its N-terminal ATP-binding site.•Potent synergistic cancer cell growth inhibition both in vitro and in vivo.•Compound 3 induces apoptosis and cell cycle arrest in Ewing sarcoma cells. 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 (IC50 = 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.