New Class of Hsp90 C-Terminal Domain Inhibitors with Anti-tumor Properties against Triple-Negative Breast Cancer,Journal of Medicinal Chemistry

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New Class of Hsp90 C-Terminal Domain Inhibitors with Anti-tumor Properties against Triple-Negative Breast Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-23 , DOI: 10.1021/acs.jmedchem.4c00932
Živa Zajec ₁ , Jaka Dernovšek ₁ , Jernej Cingl ₁ , Iza Ogris ₂ , Marius Gedgaudas ₃ , Asta Zubrienė ₃ , Ana Mitrović _{1,

4} , Simona Golič Grdadolnik ₂ , Martina Gobec ₁ , Tihomir Tomašič ₁

Affiliation

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.

中文翻译：

新型 Hsp90 C 端结构域抑制剂，具有针对三阴性乳腺癌的抗肿瘤特性

三阴性乳腺癌（TNBC）仍然是治疗挑战，需要创新疗法。 Hsp90 对于许多致癌蛋白的稳定性至关重要，已成为一个有前途的治疗靶点。在本研究中，我们提出了 Hsp90 C 末端结构域 (CTD) 抑制剂TVS21的优化。采用生化方法、NMR 结合研究和分子建模来研究代表性类似物与 Hsp90 的结合。新合成的类似物在乳腺癌细胞系（包括 MDA-MB-231 TNBC 细胞系）中显示出增强的抗增殖活性。化合物89和104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，而不诱导热休克反应。在体内，化合物89显示出与临床候选药物 AUY922 相当的功效，并且在 TNBC 异种移植模型中具有更好的安全性。这些结果凸显了 Hsp90 CTD 抑制剂用于 TNBC 治疗的前景，有可能填补重大的治疗空白。

更新日期：2024-07-23

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