Optimisation of pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives as novel Hsp90 C-terminal domain inhibitors against Ewing sarcoma

Zajec, Živa (author), Dernovšek, Jaka (author), Distel, Martin (author), Gobec, Martina (author), Tomašič, Tihomir (author)

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 IC$_{50}$ 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.

• Language: English
• Keywords: cancer, Ewing sarcoma, Hsp90, inhibitor, molecular modelling
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: 16 str.
• Numbering: Vol. 131, art. 106311
• PID: 20.500.12556/RUL-143238
• UDC: 615.2:616-006.34
• ISSN on article: 0045-2068
• DOI: 10.1016/j.bioorg.2022.106311
• COBISS.SI-ID: 132438019
• Publication date in RUL: 09.12.2022

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: Ewingov sarkom, Hsp90, inhibitorji, molekularno modeliranje, maligni tumor kosti, rak, medicina, osteosarkom

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: P1-0208
• Name: Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

• Funder: ARRS - Slovenian Research Agency
• Project number: J1-1717
• Name: Razvoj novih zaviralcev Hsp90 s protitumornim delovanjem