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Design, Synthesis, and Biological Evaluation of Potent EZH2/LSD1 Dual Inhibitors for Prostate Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-28 , DOI: 10.1021/acs.jmedchem.4c01250 Meiling Le 1 , Wenhua Lu 1 , Xiaozhuo Tan 1 , Bingling Luo 1 , Tiantian Yu 1 , Yameng Sun 1 , Zhirong Guo 1 , Peng Huang 1 , Daqian Zhu 2 , Qiang Wu 3 , A Ganesan 4 , Shijun Wen 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-28 , DOI: 10.1021/acs.jmedchem.4c01250 Meiling Le 1 , Wenhua Lu 1 , Xiaozhuo Tan 1 , Bingling Luo 1 , Tiantian Yu 1 , Yameng Sun 1 , Zhirong Guo 1 , Peng Huang 1 , Daqian Zhu 2 , Qiang Wu 3 , A Ganesan 4 , Shijun Wen 1
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As histone modification enzymes, EZH2 mediates H3K27 trimethylation (H3K27me3), whereas LSD1 removes methyl groups from H3K4me1/2 and H3K9me1/2. Synergistic anticancer effects of combining inhibitors of these two enzymes are observed in leukemia and prostate cancer. Thus, a series of EZH2/LSD1 dual inhibitors are designed and synthesized to evaluate their anticancer activity. After the structure–activity study, one of the best compounds, ML234, displayed excellent antiproliferative capacity against prostate cancer cell lines LNCAP, PC3, and 22RV1. Enzymatic assays ascertained that the anticancer potency of ML234 was mediated through coinhibition of EZH2 and LSD1. Moreover, the accumulation of H3K4me2 and H3K9me2 and the decrease of H3K27me3 induced by ML234 were verified by Western blot analysis. More importantly, the compound remarkably suppressed the tumor growth and enhanced the therapeutic efficacy of clinical drug enzalutamide in the 22RV1 xenograft mouse model, indicating that it may have potential as an anticancer agent in prostate cancer.
中文翻译：
前列腺癌有效 EZH2/LSD1 双重抑制剂的设计、合成和生物学评价
作为组蛋白修饰酶，EZH2 介导 H3K27 三甲基化 (H3K27me3)，而 LSD1 则去除 H3K4me1/2 和 H3K9me1/2 中的甲基。在白血病和前列腺癌中观察到这两种酶的组合抑制剂的协同抗癌作用。因此，设计并合成了一系列EZH2/LSD1双重抑制剂来评估其抗癌活性。经过结构-活性研究，最好的化合物之一ML234对前列腺癌细胞系 LNCAP、PC3 和 22RV1 显示出优异的抗增殖能力。酶测定确定ML234的抗癌效力是通过 EZH2 和 LSD1 的共同抑制介导的。此外，通过Western blot分析证实了ML234诱导的H3K4me2和H3K9me2的积累以及H3K27me3的减少。更重要的是，该化合物在22RV1异种移植小鼠模型中显着抑制肿瘤生长并增强临床药物恩杂鲁胺的治疗效果，表明它可能具有作为前列腺癌抗癌药物的潜力。
更新日期：2024-08-28
中文翻译：
前列腺癌有效 EZH2/LSD1 双重抑制剂的设计、合成和生物学评价
作为组蛋白修饰酶，EZH2 介导 H3K27 三甲基化 (H3K27me3)，而 LSD1 则去除 H3K4me1/2 和 H3K9me1/2 中的甲基。在白血病和前列腺癌中观察到这两种酶的组合抑制剂的协同抗癌作用。因此，设计并合成了一系列EZH2/LSD1双重抑制剂来评估其抗癌活性。经过结构-活性研究，最好的化合物之一ML234对前列腺癌细胞系 LNCAP、PC3 和 22RV1 显示出优异的抗增殖能力。酶测定确定ML234的抗癌效力是通过 EZH2 和 LSD1 的共同抑制介导的。此外，通过Western blot分析证实了ML234诱导的H3K4me2和H3K9me2的积累以及H3K27me3的减少。更重要的是，该化合物在22RV1异种移植小鼠模型中显着抑制肿瘤生长并增强临床药物恩杂鲁胺的治疗效果，表明它可能具有作为前列腺癌抗癌药物的潜力。
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