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

Povzetek

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.

Ključne besede

analize;zaviralci;fenili;rak dojk;

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: UL FFA - Fakulteta za farmacijo
UDK: 615.2:616-006:576.3
COBISS: 203626243 Povezava se bo odprla v novem oknu
ISSN: 1520-4804
Št. ogledov: 19
Št. prenosov: 4
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Slovenski jezik
Sekundarne ključne besede: Rak (medicina);Celice;
Vrsta dela (COBISS): Članek v reviji
Strani: <v tisku>
Letnik: ǂVol. ǂ
Zvezek: ǂno. ǂ
Čas izdaje: 2024
DOI: 10.1021/acs.jmedchem.4c00932
ID: 24798245