Discovery of a potent and selective proteolysis targeting chimera (PROTAC) degrader of NSD3 histone methyltransferase
Eur J Med Chem. 2022 Jun 13;239:114528. doi: 10.1016/j.ejmech.2022.114528. Online ahead of print.ABSTRACTNuclear 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 DC50 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.PMID:35717870 | DOI:10.1016/j.ejmech.2022.114528
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Yaoliang Sun Ying Zhang Xiaoai Chen Aisong Yu Wenhao Du Yuting Huang Feifei Wu Lei Yu Jiayi Li Cuiyun Wen Hong Yang Qiongyu Shi Meiyu Geng Xun Huang Shilin Xu Source Type: research