The rational installation of pharmacophores targeting HSP90 and LSD1 axes has achieved significant anti-cancer capacity in prostate and colorectal cancer. Among the series of hybrids, inhibitor exhibited remarkable anti-proliferative activity against prostate cancer cell lines PC-3 and DU145, with GI values of 0.24 and 0.30 μM, respectively. It demonstrated notable efficacy in combinatorial attack and cell death initiation towards apoptosis. The cell death process was mediated by PARP induction and γH2AX signaling, and was also characterized as caspase-dependent and Bcl-xL/Bax-independent. Notably, no difference in eye size or morphology was observed in the zebrafish treated with compound compared to the reference group (AUY922). The profound treatment response in docetaxel-resistant PC-3 cells highlighted the dual inhibitory ability in improving docetaxel sensitivity. Additionally, at a minimum concentration of 1.25 μM, compound effectively inhibited the growth of patient-derived colorectal cancer (CRC) organoids for up to 10 days . Together, the designed HSP90/LSD1 inhibitors present a novel route and significant clinical value for anti-cancer drug therapy.

中文翻译：

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针对前列腺癌以及患者来源的结直肠类器官的 HSP90/LSD1 双重抑制剂


针对HSP90和LSD1轴的药效团的合理安装在前列腺癌和结直肠癌中取得了显着的抗癌能力。在该系列杂合体中，抑制剂对前列腺癌细胞系PC-3和DU145表现出显着的抗增殖活性，GI值分别为0.24和0.30 μM。它在组合攻击和细胞死亡启动至细胞凋亡方面表现出显着的功效。细胞死亡过程由 PARP 诱导和 γH2AX 信号传导介导，并且还具有 caspase 依赖性和 Bcl-xL/Bax 独立性。值得注意的是，与参考组（AUY922）相比，用化合物处理的斑马鱼的眼睛大小或形态没有观察到差异。多西紫杉醇耐药性 PC-3 细胞的深刻治疗反应凸显了提高多西紫杉醇敏感性的双重抑制能力。此外，在 1.25 μM 的最低浓度下，化合物可有效抑制患者来源的结直肠癌 (CRC) 类器官的生长长达 10 天。总之，设计的 HSP90/LSD1 抑制剂为抗癌药物治疗提供了一种新的途径和重要的临床价值。