20.500.12556/RUL-161038 Exploration and optimisation of structure-activity relationships of new triazole-based C-terminal Hsp90 inhibitors towards in vivo anticancer potency The development of new anticancer agents is one of the most urgent topics in drug discovery. Inhibition of molecular chaperone Hsp90 stands out as an approach that affects various oncogenic proteins in different types of cancer. These proteins rely on Hsp90 to obtain their functional structure, and thus Hsp90 is indirectly involved in the pathophysiology of cancer. However, the most studied ATP-competitive inhibition of Hsp90 at the N-terminal domain has proven to be largely unsuccessful clinically. Therefore, research has shifted towards Hsp90 C-terminal domain (CTD) inhibitors, which are also the focus of this study. Our recent discovery of compound C has provided us with a starting point for exploring the structure-activity relationship and optimising this new class of triazole-based Hsp90 inhibitors. This investigation has ultimately led to a library of 33 analogues of C that have suitable physicochemical properties and several inhibit the growth of different cancer types in the low micromolar range. Inhibition of Hsp90 was confirmed by biophysical and cellular assays and the binding epitopes of selected inhibitors were studied by STD NMR. Furthermore, the most promising Hsp90 CTD inhibitor 5x was shown to induce apoptosis in breast cancer (MCF-7) and Ewing sarcoma (SK-N-MC) cells while inducing cause cell cycle arrest in MCF-7 cells. In MCF-7 cells, it caused a decrease in the levels of ERα and IGF1R, known Hsp90 client proteins. Finally, 5x was tested in zebrafish larvae xenografted with SK-N-MC tumour cells, where it limited tumour growth with no obvious adverse effects on normal zebrafish development. cancer Hsp90 inhibitor Ewing sarcoma zebrafish Hsp90 inhibitorji Ewingov sarkom cebrica rak medicina farmacevtska kemija true false true Angleški jezik Slovenski jezik Članek v reviji 2024-09-06 10:01:39 2024-09-06 10:01:49 2025-08-08 13:33:35 0000-00-00 00:00:00 2024 0 0 29 str. art. 116941 Vol. 177 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54:616-006 0753-3322 10.1016/j.biopha.2024.116941 199197699 1-s2.0-S0753332224008254-main.pdf 1-s2.0-S0753332224008254-main.pdf 1 0D1936D95974FE1AB616DAF8877C61A5 23d57fac6002ab254886f9fa8a82b07cd5887d93d6b3400b0c3bb60ea101e248 5a9ee220-6c28-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=189896 https://www.sciencedirect.com/science/article/pii/S0753332224008254 1 40b547f3-6c26-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=189890 Fakulteta za farmacijo 0 0 0