Discovery of new Hsp90–Cdc37 protein–protein interaction inhibitors : in silico screening and optimization of anticancer activity

Dernovšek, Jaka (author), Gradišek, Nina (author), Zajec, Živa (author), Urbančič, Dunja (author), Cingl, Jernej (author), Goričan, Tjaša (author), Golič Grdadolnik, Simona (author), Tomašič, Tihomir (author)

The interaction between heat shock protein 90 (Hsp90) and Hsp90 co-chaperone cell-division cycle 37 (Cdc37) is crucial for the folding and maturation of several oncogenic proteins, particularly protein kinases. This makes the inhibition of this protein–protein interaction (PPI) an interesting target for developing new anticancer compounds. However, due to the large interaction surface, developing PPI inhibitors is challenging. In this work, we describe the discovery of new Hsp90–Cdc37 PPI inhibitors using a ligand-based virtual screening approach. Initial hit compounds showed Hsp90 binding, resulting in anticancer activity in the MCF-7 breast cancer cell line. To optimize their antiproliferative effect, 35 analogs were prepared. Binding affinity for Hsp90 was determined for the most promising compounds, 8c (K$_d$ = 70.8 μM) and 13g (K$_d$ = 73.3 μM), both of which interfered with the binding of Cdc37 to Hsp90. This resulted in anticancer activity against Ewing sarcoma (SK-N-MC), breast cancer (MCF-7), and leukemia (THP-1) cell lines in vitro. Furthermore, compounds 8c and 13g demonstrated the ability to induce apoptosis in the Ewing sarcoma cell line and caused a decrease in the levels of several known Hsp90 client proteins in MCF-7 cells, all without inducing the heat shock response.

• Language: English
• Keywords: protein 90 (Hsp90), inhibition of protein–protein interaction, virtual screening, ligand-based pharmacophore models
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: Str. 28347–28375
• Numbering: Vol. 14, iss. 39
• PID: 20.500.12556/RUL-162175
• UDC: 615.4:54
• ISSN on article: 2046-2069
• DOI: 10.1039/D4RA05878J
• COBISS.SI-ID: 206551811
• Publication date in RUL: 19.09.2024

Record is a part of a journal

• Title: RSC advances
• Publisher: RSC Publishing
• ISSN: 2046-2069
• COBISS.SI-ID: 2513252

Licences

• License: CC BY 3.0, Creative Commons Attribution 3.0 Unported
• Link: https://creativecommons.org/licenses/by/3.0/deed.en
• Description: You are free to reproduce and redistribute the material in any medium or format. You are free to remix, transform, and build upon the material for any purpose, even commercially. You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.

Secondary language

• Language: Slovenian
• Keywords: zaviralci interakcije protein-protein, virtualni pregled, farmakoforski modeli na osnovi ligandov, protein 90 (Hsp90), farmacevtska kemija