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

Povzetek

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.

Ključne besede

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

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: UL FFA - Fakulteta za farmacijo
UDK: 616-006-085
COBISS: 73315587 Povezava se bo odprla v novem oknu
ISSN: 1999-4923
Št. ogledov: 127
Št. prenosov: 58
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);Zdravljenje;
Vrsta dela (COBISS): Članek v reviji
Strani: str. 1-31
Letnik: ǂVol. ǂ13
Zvezek: ǂiss. ǂ8
Čas izdaje: 2021
DOI: 10.3390/pharmaceutics13081283
ID: 15003872