Structure-activity relationships of benzothiazole-based Hsp90 C-terminal-domain inhibitors

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

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.

• Language: English
• Keywords: allostery, Hsp90, benzothiazole, cancer, inhibitor, cancer therapy
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2021
• Number of pages: 30 str.
• Numbering: Vol. 13, iss. 8, art. 1283
• PID: 20.500.12556/RUL-136079
• UDC: 616-006-085
• ISSN on article: 1999-4923
• DOI: 10.3390/pharmaceutics13081283
• COBISS.SI-ID: 73315587
• Publication date in RUL: 11.04.2022

Record is a part of a journal

• Title: Pharmaceutics
• Shortened title: Pharmaceutics
• Publisher: MDPI
• ISSN: 1999-4923
• COBISS.SI-ID: 517949977

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 17.08.2021

Secondary language

• Language: Slovenian
• Keywords: zaviralci, benzotiazol, alosterija, rak, zdravljenje

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: P1-0208
• Name: Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

• Funder: ARRS - Slovenian Research Agency
• Project number: J1-1717
• Name: Razvoj novih zaviralcev Hsp90 s protitumornim delovanjem