Živa Zajec (Author), Jaka Dernovšek (Author), Martin Distel (Author), Martina Gobec (Author), Tihomir Tomašić (Author)

Abstract

Ewing sarcoma is the second most prevalent paediatric malignant bone tumour. In most cases, it is driven by the fusion oncoprotein EWS::FLI1, which acts as an aberrant transcription factor and dysregulates gene expression. EWS::FLI1 and a large number of downstream dysregulated proteins are Hsp90 client proteins, making Hsp90 an attractive target for the treatment of Ewing sarcoma. In this article, we report a new structural class of allosteric Hsp90 C-terminal domain (CTD) inhibitors based on the virtual screening hit TVS24, which showed antiproliferative activity in the SK-N-MC Ewing sarcoma cell line with an IC50 value of 15.9±0.7 µM. The optimised compounds showed enhanced anticancer activity in the SK-N-MC cell line. Exposure of Ewing sarcoma cells to the most potent analogue 11c resulted in depletion of critical Hsp90 client proteins involved in cancer pathways such as EWS::FLI1, CDK4, RAF-1 and IGF1R, without inducing a heat shock response. The results of this study highlight Hsp90 CTD inhibitors as promising new agents for the treatment of Ewing sarcoma.

Keywords

cancer;Ewing sarcoma;Hsp90;inhibitor;molecular modelling;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FFA - Faculty of Pharmacy
UDC: 615.2:616-006.34
COBISS: 132438019 Link will open in a new window
ISSN: 0045-2068
Views: 61
Downloads: 12
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Other data

Secondary language: Slovenian
Secondary keywords: Ewingov sarkom;Hsp90;inhibitorji;molekularno modeliranje;maligni tumor kosti;Rak (medicina);Osteosarkom;
Type (COBISS): Article
Pages: str. 1-16
Issue: ǂVol. ǂ131
Chronology: 2023
DOI: 10.1016/j.bioorg.2022.106311
ID: 17361115