New class of Hsp90 C-terminal domain inhibitors with anti-tumor properties against triple-negative breast cancer

Zajec, Živa (author), Dernovšek, Jaka (author), Cingl, Jernej (author), Ogris, Iza (author), Gedgaudas, Marius (author), Zubrienė, Asta (author), Mitrović, Ana (author), Golič Grdadolnik, Simona (author), Gobec, Martina (author), Tomašič, Tihomir (author)

Triple-negative breast cancer (TNBC) remains a treatment challenge and requires innovative therapies. Hsp90, crucial for the stability of numerous oncogenic proteins, has emerged as a promising therapeutic target. In this study, we present the optimization of the Hsp90 C-terminal domain (CTD) inhibitor TVS21. Biochemical methods, NMR binding studies, and molecular modeling were employed to investigate the binding of representative analogs to Hsp90. The newly synthesized analogs showed increased antiproliferative activity in breast cancer cell lines, including the MDA-MB-231 TNBC cell line. Compounds 89 and 104 proved to be the most effective, inducing apoptosis, slowing proliferation, and degrading key oncogenic proteins without inducing a heat shock response. In vivo, compound 89 showed comparable efficacy to the clinical candidate AUY922 and a better safety profile in a TNBC xenograft model. These results highlight the promise of Hsp90 CTD inhibitors for TNBC therapy, potentially filling a significant treatment gap.

• Language: English
• Keywords: assays, cancer, cells, inhibitors, phenyls
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: Str. 12984–13018
• Numbering: Vol. 67, iss. 15
• PID: 20.500.12556/RUL-160213
• UDC: 615.2:616-006:576.3
• ISSN on article: 1520-4804
• DOI: 10.1021/acs.jmedchem.4c00932
• COBISS.SI-ID: 203626243
• Publication date in RUL: 23.08.2024

Record is a part of a journal

• Title: Journal of medicinal chemistry
• Shortened title: J. med. chem.
• Publisher: American Chemical Society
• ISSN: 1520-4804
• COBISS.SI-ID: 512806681

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.

Secondary language

• Language: Slovenian
• Keywords: analize, zaviralci, fenili, rak dojk, rak, medicina, celice