20.500.12556/RUL-143238 Optimisation of pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives as novel Hsp90 C-terminal domain inhibitors against Ewing sarcoma 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. cancer Ewing sarcoma Hsp90 inhibitor molecular modelling Ewingov sarkom Hsp90 inhibitorji molekularno modeliranje maligni tumor kosti rak medicina osteosarkom true false true Angleški jezik Slovenski jezik Članek v reviji 2022-12-09 07:47:16 2022-12-09 07:47:19 2023-01-20 11:24:16 0000-00-00 00:00:00 2023 0 0 16 str. Vol. 131, art. 106311 2023 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.2:616-006.34 0045-2068 10.1016/j.bioorg.2022.106311 132438019 1-s2.0-S0045206822007179-main.pdf 1-s2.0-S0045206822007179-main.pdf 1 F5A22E168EBA873144FDBCFED68212AB 0f3c0502867df2ea9bb2d1d9abe9d001dc366a442b75dba2ecc6f59d47acef42 474eae91-778d-11ed-9c94-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=164858 https://www.sciencedirect.com/science/article/pii/S0045206822007179 1 2a2f91f9-778d-11ed-9c94-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=164857 Fakulteta za farmacijo 0 0 0