Exploration and optimisation of structure-activity relationships of new triazole-based C-terminal Hsp90 inhibitors towards in vivo anticancer potency

• Published in: Biomedicine & pharmacotherapy Vol. 177; p. 116941
• Main Authors: Dernovšek, Jaka, Zajec, Živa, Poje, Goran, Urbančič, Dunja, Sturtzel, Caterina, Goričan, Tjaša, Grissenberger, Sarah, Ciura, Krzesimir, Woziński, Mateusz, Gedgaudas, Marius, Zubrienė, Asta, Grdadolnik, Simona Golič, Mlinarič-Raščan, Irena, Rajić, Zrinka, Cotman, Andrej Emanuel, Zidar, Nace, Distel, Martin, Tomašič, Tihomir
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-08-2024; Elsevier
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Ewing sarcoma; Hsp90; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - metabolism; Humans; Inhibitor; MCF-7 Cells; Structure-Activity Relationship; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; Zebrafish; Hsp90; Zebrafish; Ewing sarcoma; Inhibitor; Cancer
• ISSN: 0753-3322; 1950-6007; 1950-6007
• DOI: 10.1016/j.biopha.2024.116941

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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•A library of new triazoles as Hsp90 C-terminal inhibitors was prepared.•Several compounds inhibited the growth of various cancer cells in vitro.•Binding mode of 5x to Hsp90 was studied by TR-FRET, MST, STD NMR and MD simulations.•5x decreased the levels of Hsp90 clients in MCF-7 breast cancer cells.•5x inhibited the growth of Ewing sarcoma in vivo in zebrafish larvae xenografts.