PUBLICATION
First dual inhibitors of human topoisomerase IIα and Hsp90 C-terminal domain inhibit the growth of Ewing sarcoma in vitro and in vivo
- Authors
- Dernov?ek, J., Urban?i?, D., Zajec, ?., Sturtzel, C., Grissenberger, S., Wenninger-Weinzierl, A., Gedgaudas, M., Zubrien?, A., Gori?an, T., Goli? Grdadolnik, S., Skok, ?., Ila?, J., Distel, M., Zidar, N., Toma?i?, T.
- ID
- ZDB-PUB-241013-7
- Date
- 2024
- Source
- Bioorganic chemistry 153: 107850107850 (Journal)
- Registered Authors
- Distel, Martin, Grissenberger, Sarah, Sturtzel, Caterina, Wenninger-Weinzierl, Andrea
- Keywords
- Cancer, Ewing sarcoma, Hsp90, Inhibitor, Topoisomerase II?, Zebrafish
- MeSH Terms
-
- Antigens, Neoplasm/metabolism
- Zebrafish*
- Cell Line, Tumor
- Antineoplastic Agents*/chemical synthesis
- Antineoplastic Agents*/chemistry
- Antineoplastic Agents*/pharmacology
- Humans
- HSP90 Heat-Shock Proteins*/antagonists & inhibitors
- HSP90 Heat-Shock Proteins*/metabolism
- Animals
- DNA-Binding Proteins/antagonists & inhibitors
- DNA-Binding Proteins/metabolism
- Cell Proliferation*/drug effects
- Sarcoma, Ewing*/drug therapy
- Sarcoma, Ewing*/metabolism
- Sarcoma, Ewing*/pathology
- Dose-Response Relationship, Drug
- DNA Topoisomerases, Type II*/metabolism
- Topoisomerase II Inhibitors*/chemical synthesis
- Topoisomerase II Inhibitors*/chemistry
- Topoisomerase II Inhibitors*/pharmacology
- Apoptosis/drug effects
- Drug Screening Assays, Antitumor
- Structure-Activity Relationship
- Molecular Structure
- PubMed
- 39395321 Full text @ Bioorg. Chem.
Citation
Dernov?ek, J., Urban?i?, D., Zajec, ?., Sturtzel, C., Grissenberger, S., Wenninger-Weinzierl, A., Gedgaudas, M., Zubrien?, A., Gori?an, T., Goli? Grdadolnik, S., Skok, ?., Ila?, J., Distel, M., Zidar, N., Toma?i?, T. (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. 153:107850107850.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping