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Exploration and optimisation of structure-activity relationships of new triazole-based C-terminal Hsp90 inhibitors towards in vivo anticancer potency.
Dernovsek, Jaka; Zajec, Ziva; Poje, Goran; Urbancic, Dunja; Sturtzel, Caterina; Gorican, Tjasa; Grissenberger, Sarah; Ciura, Krzesimir; Wozinski, Mateusz; Gedgaudas, Marius; Zubriene, Asta; Grdadolnik, Simona Golic; Mlinaric-Rascan, Irena; Rajic, Zrinka; Cotman, Andrej Emanuel; Zidar, Nace; Distel, Martin; Tomasic, Tihomir.
Afiliación
  • Dernovsek J; Faculty of Pharmacy, University of Ljubljana, Askerceva cesta 7, Ljubljana 1000, Slovenia.
  • Zajec Z; Faculty of Pharmacy, University of Ljubljana, Askerceva cesta 7, Ljubljana 1000, Slovenia.
  • Poje G; Faculty of Pharmacy and Biochemistry, University of Zagreb, Ante Kovacica 1, Zagreb 10000, Croatia.
  • Urbancic D; Faculty of Pharmacy, University of Ljubljana, Askerceva cesta 7, Ljubljana 1000, Slovenia.
  • Sturtzel C; St. Anna Children's Cancer Research Institute, Zimmermannplatz 10, Vienna 1090, Austria.
  • Gorican T; Laboratory for Molecular Structural Dynamics, Theory Department, National Institute of Chemistry, Hajdrihova 19, Ljubljana 1001, Slovenia.
  • Grissenberger S; St. Anna Children's Cancer Research Institute, Zimmermannplatz 10, Vienna 1090, Austria.
  • Ciura K; Department of Physical Chemistry, Medical University of Gdansk, Gdansk 80-416, Poland.
  • Wozinski M; Department of Physical Chemistry, Medical University of Gdansk, Gdansk 80-416, Poland.
  • Gedgaudas M; Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Sauletekio al. 7, Vilnius LT-10257, Lithuania.
  • Zubriene A; Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Sauletekio al. 7, Vilnius LT-10257, Lithuania.
  • Grdadolnik SG; Laboratory for Molecular Structural Dynamics, Theory Department, National Institute of Chemistry, Hajdrihova 19, Ljubljana 1001, Slovenia.
  • Mlinaric-Rascan I; Faculty of Pharmacy, University of Ljubljana, Askerceva cesta 7, Ljubljana 1000, Slovenia.
  • Rajic Z; Faculty of Pharmacy and Biochemistry, University of Zagreb, Ante Kovacica 1, Zagreb 10000, Croatia.
  • Cotman AE; Faculty of Pharmacy, University of Ljubljana, Askerceva cesta 7, Ljubljana 1000, Slovenia.
  • Zidar N; Faculty of Pharmacy, University of Ljubljana, Askerceva cesta 7, Ljubljana 1000, Slovenia.
  • Distel M; St. Anna Children's Cancer Research Institute, Zimmermannplatz 10, Vienna 1090, Austria.
  • Tomasic T; Faculty of Pharmacy, University of Ljubljana, Askerceva cesta 7, Ljubljana 1000, Slovenia. Electronic address: tihomir.tomasic@ffa.uni-lj.si.
Biomed Pharmacother ; 177: 116941, 2024 Aug.
Article en En | MEDLINE | ID: mdl-38889640
ABSTRACT
The development of new anticancer agents is one of the most urgent topics in drug discovery. Inhibition of molecular chaperone Hsp90 stands out as an approach that affects various oncogenic proteins in different types of cancer. These proteins rely on Hsp90 to obtain their functional structure, and thus Hsp90 is indirectly involved in the pathophysiology of cancer. However, the most studied ATP-competitive inhibition of Hsp90 at the N-terminal domain has proven to be largely unsuccessful clinically. Therefore, research has shifted towards Hsp90 C-terminal domain (CTD) inhibitors, which are also the focus of this study. Our recent discovery of compound C has provided us with a starting point for exploring the structure-activity relationship and optimising this new class of triazole-based Hsp90 inhibitors. This investigation has ultimately led to a library of 33 analogues of C that have suitable physicochemical properties and several inhibit the growth of different cancer types in the low micromolar range. Inhibition of Hsp90 was confirmed by biophysical and cellular assays and the binding epitopes of selected inhibitors were studied by STD NMR. Furthermore, the most promising Hsp90 CTD inhibitor 5x was shown to induce apoptosis in breast cancer (MCF-7) and Ewing sarcoma (SK-N-MC) cells while inducing cause cell cycle arrest in MCF-7 cells. In MCF-7 cells, it caused a decrease in the levels of ERα and IGF1R, known Hsp90 client proteins. Finally, 5x was tested in zebrafish larvae xenografted with SK-N-MC tumour cells, where it limited tumour growth with no obvious adverse effects on normal zebrafish development.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Triazoles / Pez Cebra / Apoptosis / Proteínas HSP90 de Choque Térmico / Antineoplásicos Límite: Animals / Humans Idioma: En Revista: Biomed Pharmacother Año: 2024 Tipo del documento: Article Pais de publicación: Francia
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Triazoles / Pez Cebra / Apoptosis / Proteínas HSP90 de Choque Térmico / Antineoplásicos Límite: Animals / Humans Idioma: En Revista: Biomed Pharmacother Año: 2024 Tipo del documento: Article Pais de publicación: Francia