20.500.12556/RUL-160213 New class of Hsp90 C-terminal domain inhibitors with anti-tumor properties against triple-negative breast cancer Triple-negative breast cancer (TNBC) remains a treatment challenge and requires innovative therapies. Hsp90, crucial for the stability of numerous oncogenic proteins, has emerged as a promising therapeutic target. In this study, we present the optimization of the Hsp90 C-terminal domain (CTD) inhibitor TVS21. Biochemical methods, NMR binding studies, and molecular modeling were employed to investigate the binding of representative analogs to Hsp90. The newly synthesized analogs showed increased antiproliferative activity in breast cancer cell lines, including the MDA-MB-231 TNBC cell line. Compounds 89 and 104 proved to be the most effective, inducing apoptosis, slowing proliferation, and degrading key oncogenic proteins without inducing a heat shock response. In vivo, compound 89 showed comparable efficacy to the clinical candidate AUY922 and a better safety profile in a TNBC xenograft model. These results highlight the promise of Hsp90 CTD inhibitors for TNBC therapy, potentially filling a significant treatment gap. assays cancer cells inhibitors phenyls analize zaviralci fenili rak dojk rak medicina celice true false true Angleški jezik Slovenski jezik Članek v reviji 2024-08-23 09:32:40 2024-08-23 09:32:42 2024-08-24 04:06:55 0000-00-00 00:00:00 2024 0 0 Str. 12984–13018 iss. 15 Vol. 67 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.2:616-006:576.3 1520-4804 10.1021/acs.jmedchem.4c00932 203626243 zajec-et-al-2024-new-class-of-hsp90-c-terminal-domain-inhibitors-with-anti-tumor-properties-against-triple-negative.pdf zajec-et-al-2024-new-class-of-hsp90-c-terminal-domain-inhibitors-with-anti-tumor-properties-against-triple-negative.pdf 1 8DD2DFC653E196969675EFE5E7AD6FC6 a35c3da28a42c2c79684215ecaf498cef2b4a7490fd6868f4a93014ec603fbad 21e4c265-6122-11ef-8f74-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=188756 https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00932 1 aae9f995-6121-11ef-8f74-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=188755 Fakulteta za farmacijo 0 0 0