Optimisation of pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives as novel Hsp90 C-terminal domain inhibitors against Ewing sarcoma
| العنوان: | Optimisation of pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives as novel Hsp90 C-terminal domain inhibitors against Ewing sarcoma |
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| المؤلفون: | Živa Zajec, Jaka Dernovšek, Martin Distel, Martina Gobec, Tihomir Tomašič |
| المصدر: | Bioorganic chemistry, vol. 131, 106311, 2023. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Ewingov sarkom, inhibitorji, osteosarkom, Organic Chemistry, Hsp90, Biochemistry, udc:615.2:616-006.34, molecular modelling, molekularno modeliranje, inhibitor, Drug Discovery, rak, cancer, maligni tumor kosti, Molecular Biology, Ewing sarcoma, medicina |
| الوصف: | 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. |
| وصف الملف: | application/pdf; text/url |
| تدمد: | 1090-2120 0045-2068 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::202fb8afb17b92acf1038d72b010e2ba https://pubmed.ncbi.nlm.nih.gov/36495678 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....202fb8afb17b92acf1038d72b010e2ba |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10902120 00452068 |
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