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具有抗三阴性乳腺癌特性的新型Hsp90 C末端结构域抑制剂

New Class of Hsp90 C-Terminal Domain Inhibitors with Anti-tumor Properties against Triple-Negative Breast Cancer.

作者信息

Zajec Živa, Dernovšek Jaka, Cingl Jernej, Ogris Iza, Gedgaudas Marius, Zubrienė Asta, Mitrović Ana, Golič Grdadolnik Simona, Gobec Martina, Tomašič Tihomir

机构信息

Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.

Laboratory for Molecular Structural Dynamics, Theory Department, National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia.

出版信息

J Med Chem. 2024 Aug 8;67(15):12984-13018. doi: 10.1021/acs.jmedchem.4c00932. Epub 2024 Jul 23.

DOI:10.1021/acs.jmedchem.4c00932
PMID:39042910
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11320583/
Abstract

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 . 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 and proved to be the most effective, inducing apoptosis, slowing proliferation, and degrading key oncogenic proteins without inducing a heat shock response. In vivo, compound 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.

摘要

三阴性乳腺癌（TNBC）仍然是一个治疗难题，需要创新疗法。热休克蛋白90（Hsp90）对众多致癌蛋白的稳定性至关重要，已成为一个有前景的治疗靶点。在本研究中，我们展示了热休克蛋白90 C端结构域（CTD）抑制剂的优化。采用生化方法、核磁共振结合研究和分子建模来研究代表性类似物与热休克蛋白90的结合。新合成的类似物在乳腺癌细胞系中显示出增强的抗增殖活性，包括MDA-MB-231三阴性乳腺癌细胞系。化合物 和 被证明是最有效的，可诱导细胞凋亡、减缓增殖并降解关键致癌蛋白，而不会诱导热休克反应。在体内，化合物 在三阴性乳腺癌异种移植模型中显示出与临床候选药物AUY922相当的疗效和更好的安全性。这些结果突出了热休克蛋白90 CTD抑制剂在三阴性乳腺癌治疗中的前景，可能填补一个重大的治疗空白。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2461/11320583/cd4a5e88eca1/jm4c00932_0011.jpg
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