Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.
Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.
Eur J Med Chem. 2022 Aug 5;238:114462. doi: 10.1016/j.ejmech.2022.114462. Epub 2022 May 20.
EZH2 is usually overexpressed in TNBC and other tumors, which has a great influence on the occurrence, development and prognosis of tumors. However, current EZH2 inhibitors, including Tazemetostat and GSK126, affect the methyl catalytic capacity of EZH2 and have little effect on the tumorigenic activity of EZH2 itself, resulting in poor efficacy against most solid tumors. Herein, we designed and optimized proteolytic targeting chimeras (PROTACs) precision targeting EZH2. The most active PROTAC molecule U3i has a high affinity for PRC2 complex (K = 16.19 nM) and show good inhibitory effects on MDA-MB-231 (IC = 0.57 μM) and MDA-MB-468 (IC = 0.38 μM) cells. Compared with that of the GSK126, the growth inhibitory activities of U3i against these two TNBC cells increased by approximately 20- and 30-fold. Further studies showed that U3i can degrade PRC2 complex in TNBC cells, induce apoptosis, and cause little damage to normal cells. Therefore, U3i is a potential anticancer molecule for TNBC treatment.
EZH2 在三阴性乳腺癌和其他肿瘤中通常过表达，对肿瘤的发生、发展和预后有很大影响。然而，目前的 EZH2 抑制剂，包括 Tazemetostat 和 GSK126，会影响 EZH2 的甲基化催化能力，对 EZH2 本身的致瘤活性影响不大，导致对大多数实体瘤的疗效不佳。在此，我们设计并优化了针对 EZH2 的蛋白水解靶向嵌合体（PROTAC）。最有效的 PROTAC 分子 U3i 对 PRC2 复合物具有高亲和力（K=16.19 nM），对 MDA-MB-231（IC=0.57 μM）和 MDA-MB-468（IC=0.38 μM）细胞具有良好的抑制作用。与 GSK126 相比，U3i 对这两种 TNBC 细胞的生长抑制活性分别增加了约 20 倍和 30 倍。进一步的研究表明，U3i 可以使 TNBC 细胞中的 PRC2 复合物降解，诱导细胞凋亡，对正常细胞的损伤很小。因此，U3i 是一种治疗 TNBC 的潜在抗癌分子。
