发现首个在体内具有强效抗肿瘤作用的 ROCK/HDAC 双靶点抑制剂，可触发抗肿瘤免疫力

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2024-11-10 DOI:10.1021/acs.jmedchem.4c02183

Churu Mao, Jiebin Fang, Shijie Zou, Yun Huang, Xiaoming Chen, Xia Ding, Zhangyun Fang, Ningjing Zhang, Yijie Lou, Zhe Chen, Wanjing Ding, Zhongjun Ma

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引用次数: 0

摘要

三阴性乳腺癌（TNBC）是一种侵袭性极强的异质性恶性肿瘤。目前，多靶点药物是治疗 TNBC 的一种很有前景的方法。利用组合化学策略构建虚拟筛选数据库，发现了 ROCK/HDAC 双靶向苯并噻吩化合物。值得注意的是，化合物 10h 能有效抑制 ROCK1/2 和 HDAC1/2/3/6/8，同时对乳腺癌细胞具有强大的抗增殖活性。在乳腺癌小鼠正位模型中，10h 能显著抑制肿瘤生长，且无明显毒性。重要的是，10h 能诱导免疫原性细胞死亡（ICD），促进树突状细胞（DC）成熟，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ROCK/HDAC双靶点抑制剂，是治疗TNBC的一种很有前景的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Discovery of the First-in-Class Dual-Target ROCK/HDAC Inhibitor with Potent Antitumor Efficacy in Vivo That Trigger Antitumor Immunity

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Discovery of the First-in-Class Dual-Target ROCK/HDAC Inhibitor with Potent Antitumor Efficacy in Vivo That Trigger Antitumor Immunity

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.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.