Jaka Dernovšek (Author), Živa Zajec (Author), Martina Durcik (Author), Lucija Peterlin-Mašič (Author), Martina Gobec (Author), Nace Zidar (Author), Tihomir Tomašić (Author)

Abstract

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 IC50, with the most potent being compounds 5g and 9i (IC50, 2.8 - 0.1, 3.9 - 0.1 [micro]M, 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.

Keywords

zaviralci;benzotiazol;alosterija;allosteric;Hsp90;benzothiazole;cancer;inhibitor;cancer therapy;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FFA - Faculty of Pharmacy
UDC: 616-006-085
COBISS: 73315587 Link will open in a new window
ISSN: 1999-4923
Views: 127
Downloads: 58
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Other data

Secondary language: Slovenian
Secondary keywords: Rak (medicina);Zdravljenje;
Type (COBISS): Article
Pages: str. 1-31
Volume: ǂVol. ǂ13
Issue: ǂiss. ǂ8
Chronology: 2021
DOI: 10.3390/pharmaceutics13081283
ID: 15003872