State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
J Med Chem. 2024 Sep 12;67(17):15586-15605. doi: 10.1021/acs.jmedchem.4c01250. Epub 2024 Aug 28.
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, , displayed excellent antiproliferative capacity against prostate cancer cell lines LNCAP, PC3, and 22RV1. Enzymatic assays ascertained that the anticancer potency of was mediated through coinhibition of EZH2 and LSD1. Moreover, the accumulation of H3K4me2 and H3K9me2 and the decrease of H3K27me3 induced by 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.
作为组蛋白修饰酶，EZH2 介导 H3K27 三甲基化（H3K27me3），而 LSD1 则从 H3K4me1/2 和 H3K9me1/2 上去除甲基。在白血病和前列腺癌中，联合使用这两种酶抑制剂具有协同的抗癌作用。因此，设计并合成了一系列 EZH2/LSD1 双重抑制剂来评估它们的抗癌活性。经过构效关系研究，其中一种最佳化合物 ，对前列腺癌细胞系 LNCAP、PC3 和 22RV1 显示出优异的增殖抑制能力。酶活性测定证实，通过抑制 EZH2 和 LSD1 的双重抑制作用，化合物 发挥了抗癌作用。此外，通过 Western blot 分析验证了 诱导的 H3K4me2 和 H3K9me2 积累以及 H3K27me3 减少。更重要的是，该化合物显著抑制了 22RV1 异种移植小鼠模型中的肿瘤生长，并增强了临床药物恩扎鲁胺的治疗效果，表明其在前列腺癌中可能具有作为抗癌剂的潜力。
