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

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

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.

• Jezik: Angleški jezik
• Ključne besede: allostery, Hsp90, benzothiazole, cancer, inhibitor, cancer therapy
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2021
• Št. strani: 30 str.
• Številčenje: Vol. 13, iss. 8, art. 1283
• PID: 20.500.12556/RUL-136079
• UDK: 616-006-085
• ISSN pri članku: 1999-4923
• DOI: 10.3390/pharmaceutics13081283
• COBISS.SI-ID: 73315587
• Datum objave v RUL: 11.04.2022

Gradivo je del revije

• Naslov: Pharmaceutics
• Skrajšan naslov: Pharmaceutics
• Založnik: MDPI
• ISSN: 1999-4923
• COBISS.SI-ID: 517949977

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.
• Začetek licenciranja: 17.08.2021

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: zaviralci, benzotiazol, alosterija, rak, zdravljenje

Projekti

• Financer: ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
• Številka projekta: P1-0208
• Naslov: Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

• Financer: ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
• Številka projekta: J1-1717
• Naslov: Razvoj novih zaviralcev Hsp90 s protitumornim delovanjem