20.500.12556/RUL-162175 Discovery of new Hsp90–Cdc37 protein–protein interaction inhibitors in silico screening and optimization of anticancer activity 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. protein 90 (Hsp90) inhibition of protein–protein interaction virtual screening ligand-based pharmacophore models zaviralci interakcije protein-protein virtualni pregled farmakoforski modeli na osnovi ligandov protein 90 (Hsp90) farmacevtska kemija true false true Angleški jezik Slovenski jezik Članek v reviji 2024-09-19 11:38:37 2024-09-19 11:38:42 2024-09-23 03:31:38 0000-00-00 00:00:00 2024 0 0 Str. 28347–28375 iss. 39 Vol. 14 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54 2046-2069 10.1039/D4RA05878J 206551811 d4ra05878j.pdf d4ra05878j.pdf 1 221E24869DAE1537D2743892FE143CF8 afa3c0f9b6980a300c7d3670361d23a13b2db657911db27c27ca30e1e9a772d4 c1aa2a7a-766b-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=191348 https://pubs.rsc.org/en/content/articlelanding/2024/ra/d4ra05878j 1 da1cdcde-766a-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=191346 Fakulteta za farmacijo 0 0 0