20.500.12556/RUL-163948 First dual inhibitors of human topoisomerase IIα and Hsp90 C-terminal domain inhibit the growth of Ewing sarcoma in vitro and in vivo Heat shock protein 90 (Hsp90) and topoisomerase IIα (TopoIIα) are members of the GHKL protein superfamily, both with clinically validated roles as anticancer drug targets. We report the discovery of the first class of dual inhibitors targeting the ATP-binding site of TopoIIα and the C-terminal domain of Hsp90, displaying potent cancer growth inhibition both in vitro and in vivo. Initially, a known TopoIIα inhibitor, compound 3, was shown to bind to the C-terminal domain of Hsp90, but not to its ATP-binding N-terminal domain. Nineteen analogs were then prepared and evaluated to investigate the structure–activity relationships, several of which inhibited the growth of SK-N-MC Ewing sarcoma cells in vitro. Compound 3 emerged as one of the most potent growth inhibitors (IC$_{50}$ = 0.33 ± 0.04 µM), demonstrating the ability to induce apoptosis and cell cycle arrest in SK-N-MC cells in vitro, and to slow the growth of Ewing sarcoma in vivo in a zebrafish model. cancer Ewing sarcoma Hsp90 inhibitor topoisomerase IIα zebrafish rak medicina sarkom true false true Angleški jezik Slovenski jezik Članek v reviji 2024-10-14 14:23:36 2024-10-14 14:23:43 2024-10-16 03:30:11 0000-00-00 00:00:00 2024 0 0 20 str. art. 107850 Vol. 153 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616-006 0045-2068 10.1016/j.bioorg.2024.107850 209903875 1-s2.0-S0045206824007557-main.pdf 1-s2.0-S0045206824007557-main.pdf 1 52C24972AF72FFF36AB8244BFBE1DE0A 300bd9844f88911b1a64d991b12d4a4282f9a7daeee7cb82c572faa20f8a1cf6 8618d0f7-8a2a-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=193960 https://www.sciencedirect.com/science/article/pii/S0045206824007557 1 ede80541-8a26-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=193956 Fakulteta za farmacijo 0 0 0