1. Optimisation of pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives as novel Hsp90 C-terminal domain inhibitors against Ewing sarcoma
- Author
-
Živa Zajec, Jaka Dernovšek, Martin Distel, Martina Gobec, and Tihomir Tomašič
- Subjects
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 - 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 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.
- Published
- 2022