Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, PR China.
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, NO. 19A Yuquan Road, Beijing, 100049, PR China.
Eur J Med Chem. 2022 Sep 5;239:114528. doi: 10.1016/j.ejmech.2022.114528. Epub 2022 Jun 13.
Nuclear receptor binding SET domain protein 3 (NSD3) is an attractive potential target in the therapy for human cancers. Herein, we report the discovery of a series of small-molecule NSD3 degraders based on the proteolysis targeting chimera (PROTAC) strategy. The represented compound 8 induces NSD3 degradation with DC values of 1.43 and 0.94 μM in NCI-H1703 and A549 lung cancer cells, respectively, and shows selectivity over two other NSD proteins. 8 reduces histone H3 lysine 36 methylation and induces apoptosis and cell cycle arrest in lung cancer cells. Moreover, the RNA sequencing and immunohistochemistry assays showed that 8 downregulates NSD3-associated gene expression. Significantly, 8, but not 1 (a reported NSD3-PWWP antagonist) could inhibit the cell growth of NCI-H1703 and A549 cells. A single administration of 8 effectively decreases the NSD3 protein level in lung cancer xenograft models. Therefore, this study demonstrated that inducing NSD3 degradation is a more effective approach inhibiting the function of NSD3 than blocking the NSD3-PWWP domain, which may provide a potential therapeutic approach for lung cancer.
核受体结合 SET 域蛋白 3（NSD3）是人类癌症治疗中一个有吸引力的潜在靶点。在此，我们报告了一系列基于蛋白水解靶向嵌合体（PROTAC）策略的小分子 NSD3 降解剂的发现。代表性化合物 8 分别在 NCI-H1703 和 A549 肺癌细胞中诱导 NSD3 降解，DC 值为 1.43 和 0.94 μM，并且对另外两种 NSD 蛋白具有选择性。8 降低组蛋白 H3 赖氨酸 36 甲基化，并诱导肺癌细胞凋亡和细胞周期停滞。此外，RNA 测序和免疫组织化学检测表明，8 下调了与 NSD3 相关的基因表达。值得注意的是，8 而不是 1（一种报道的 NSD3-PWWP 拮抗剂）能够抑制 NCI-H1703 和 A549 细胞的生长。单次给予 8 可有效降低肺癌异种移植模型中的 NSD3 蛋白水平。因此，本研究表明，诱导 NSD3 降解比阻断 NSD3-PWWP 结构域更能有效抑制 NSD3 的功能，这可能为肺癌提供一种潜在的治疗方法。
