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

Abstract

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.

Keywords

analize;zaviralci;fenili;rak dojk;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FFA - Faculty of Pharmacy
UDC: 615.2:616-006:576.3
COBISS: 203626243 Link will open in a new window
ISSN: 1520-4804
Views: 19
Downloads: 4
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Other data

Secondary language: Slovenian
Secondary keywords: Rak (medicina);Celice;
Type (COBISS): Article
Pages: <v tisku>
Volume: ǂVol. ǂ
Issue: ǂno. ǂ
Chronology: 2024
DOI: 10.1021/acs.jmedchem.4c00932
ID: 24798245