A pharmacophore-hybridized strategy based on previously reported HSP90 C-terminal inhibitors was utilized to prepare 32 aryl/penta-1,4-dien-3-one/amine hybrids. Among them, a silicon-containing compound 1z exhibited remarkable broad-spectrum antiproliferative effects on various human breast cancer cell lines. Through fluorescence polarization and AlphaScreen-based assays, we demonstrated that 1z specifically inhibited the HSP90 C-terminus without affecting HSP90 N-terminus. Furthermore, 1z effectively inhibited the HSP90 C-terminus without inducing heat-shock response (HSR), leading to the degradation of its client proteins HER2, pAKT, AKT, and CDK4, causing G₁ arrest of MCF-7 and SKBr3 cells, and ultimately contributing to apoptosis of these cells through caspase-3, caspase-8, and caspase-9 activation. Additionally, the penta-1,4-dien-3-one linker in the hybrid, a large bulky lipophilic substitution in the aryl fragment at the 3′-site, and the presence of N-methylpiperazine as the amine fragment were identified as crucial factors that significantly contributed to the observed antiproliferative activity through structure–activity relationship (SAR) analysis. Lastly, we found that 1z exhibited superior thermostability compared to vibsanin B derivatives and good in vitro metabolic stability in simulated intestinal fluid, representing one of the few reported silicon-containing HSP90 C-terminal inhibitors.

中文翻译：

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含硅芳基/五-1,4-二烯-3-酮/胺杂化物通过靶向 HSP90 C 末端而不诱导热休克反应，对乳腺癌细胞表现出抗增殖作用

利用基于先前报道的 HSP90 C 末端抑制剂的药效团杂交策略来制备 32 个芳基/五-1,4-二烯-3-酮/胺杂化物。其中，含硅化合物1z对多种人乳腺癌细胞系表现出显着的广谱抗增殖作用。通过荧光偏振和基于 AlphaScreen 的检测，我们证明1z特异性抑制 HSP90 C 末端，而不影响 HSP90 N 末端。此外，1z有效抑制 HSP90 C 末端而不诱导热休克反应 (HSR)，导致其客户蛋白 HER2、pAKT、AKT 和 CDK4 降解，导致 MCF-7 和 SKBr3 细胞的 G 1 期停滞_，并且最终通过 caspase-3、caspase-8 和 caspase-9 激活导致这些细胞凋亡。此外，杂化物中的 penta-1,4-dien-3-one 连接体、3' 位点芳基片段中的大体积亲脂性取代以及 N-甲基哌嗪作为胺片段的存在被认为是至关重要的通过结构-活性关系（SAR）分析，对观察到的抗增殖活性有显着贡献的因素。最后，我们发现1z与vibsanin B衍生物相比表现出优异的热稳定性，并且在模拟肠液中具有良好的体外代谢稳定性，是报道的少数含硅HSP90 C末端抑制剂之一。