20.500.12556/RUL-136079 Structure-activity relationships of benzothiazole-based Hsp90 C-terminal-domain inhibitors Heat shock protein 90 (Hsp90) is a chaperone responsible for the maturation of many cancer-related proteins, and is therefore an important target for the design of new anticancer agents. Several Hsp90 N-terminal domain inhibitors have been evaluated in clinical trials, but none have been approved as cancer therapies. This is partly due to induction of the heat shock response, which can be avoided using Hsp90 C-terminal-domain (CTD) inhibition. Several structural features have been shown to be useful in the design of Hsp90 CTD inhibitors, including an aromatic ring, a cationic center and the benzothiazole moiety. This study established a previously unknown link between these structural motifs. Using ligand-based design methodologies and structure-based pharmacophore models, a library of 29 benzothiazole-based Hsp90 CTD inhibitors was prepared, and their antiproliferative activities were evaluated in MCF-7 breast cancer cells. Several showed low-micromolar IC$_{50}$, with the most potent being compounds 5g and 9i (IC$_{50}$, 2.8 ± 0.1, 3.9 ± 0.1 µM, respectively). Based on these results, a ligand-based structure–activity relationship model was built, and molecular dynamics simulation was performed to elaborate the binding mode of compound 9i. Moreover, compound 9i showed degradation of Hsp90 client proteins and no induction of the heat shock response. allostery Hsp90 benzothiazole cancer inhibitor cancer therapy zaviralci benzotiazol alosterija rak zdravljenje true false true Angleški jezik Slovenski jezik Članek v reviji 2022-04-11 10:07:05 2022-04-11 10:07:12 2022-09-15 04:13:22 0000-00-00 00:00:00 2021 0 0 30 str. iss. 8, art. 1283 Vol. 13 2021 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616-006-085 1999-4923 10.3390/pharmaceutics13081283 73315587 RAZ_Dernovsek_Jaka_2021.pdf RAZ_Dernovsek_Jaka_2021.pdf 1 FC8BE1AB9F9EBBB4203471BF6F7786A6 9643d982f9a20e4aae22f40a403ff91f1de0ce40be15aa2dd327339a7c03002e 8d5ea1dc-b96e-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=155529 https://www.mdpi.com/1999-4923/13/8/1283 1 587068ce-b96e-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=155528 Fakulteta za farmacijo 0 0 0