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

Povzetek

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.

Ključne besede

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

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: UL FFA - Fakulteta za farmacijo
UDK: 615.2:616-006.34
COBISS: 132438019 Povezava se bo odprla v novem oknu
ISSN: 0045-2068
Št. ogledov: 61
Št. prenosov: 12
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Slovenski jezik
Sekundarne ključne besede: Ewingov sarkom;Hsp90;inhibitorji;molekularno modeliranje;maligni tumor kosti;Rak (medicina);Osteosarkom;
Vrsta dela (COBISS): Članek v reviji
Strani: str. 1-16
Zvezek: ǂVol. ǂ131
Čas izdaje: 2023
DOI: 10.1016/j.bioorg.2022.106311
ID: 17361115