Triple-negative breast cancer (TNBC) represents a highly aggressive and heterogeneous malignancy. Currently, multitarget drug approaches present a promising therapeutic approach for TNBC. Utilizing a combinatorial chemistry strategy to construct a virtual screening database, dual ROCK/HDAC-targeting benzothiophene compounds were identified. Notably, compound 10h effectively inhibits ROCK1/2 and HDAC1/2/3/6/8 while demonstrating potent antiproliferative activity against breast cancer cells. In an orthotopic mouse model of breast cancer, 10h significantly suppressed tumor growth without apparent toxicity. Importantly, 10h induced immunogenic cell death (ICD), promoted dendritic cells (DCs) maturation, and activated T cells, thereby initiating antitumor immunity. In conclusion, compound 10h is a novel dual-target ROCK/HDAC inhibitor that represents a promising treatment strategy for TNBC.

中文翻译：

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发现一流的双靶点 ROCK/HDAC 抑制剂，在体内具有强大的抗肿瘤功效，可触发抗肿瘤免疫


三阴性乳腺癌 （TNBC） 是一种高度侵袭性和异质性的恶性肿瘤。目前，多靶点药物方法为 TNBC 提供了一种很有前途的治疗方法。利用组合化学策略构建虚拟筛选数据库，鉴定出双重 ROCK/HDAC 靶向苯并噻吩化合物。值得注意的是，化合物 10h 有效抑制 ROCK1/2 和 HDAC1/2/3/6/8，同时表现出对乳腺癌细胞的强大抗增殖活性。在乳腺癌的原位小鼠模型中，10h 显着抑制肿瘤生长，无明显毒性。重要的是，10 小时诱导免疫原性细胞死亡 （ICD），促进树突状细胞 （DC） 成熟，并激活 T 细胞，从而启动抗肿瘤免疫。总之，化合物 10h 是一种新型双靶点 ROCK/HDAC 抑制剂，代表了一种很有前途的 TNBC 治疗策略。