Discovery of a potent and selective proteolysis targeting chimera (PROTAC) degrader of NSD3 histone methyltransferase

Sun, YL; Zhang, Y; Chen, XA; Yu, AS; Du, WH; Huang, YT; Wu, FF; Yu, L; Li, JY; Wen, CY; Yang, H; Shi, QY; Geng, MY; Huang, X; Xu, SL

Abstract

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 DC50 values of 1.43 and 0.94 mu M 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.

Keywords: NSD3; PROTAC; Degrader; Methyltransferase

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PROTAC Linkers

PROTAC Linkers play a key role in proteolytically targeted chimera (PROTAC) degradation. PROTAC Linkers are variable structural chains that connect two key parts of the PROTAC molecule, which are connected to the target protein and ubiquitin respectively. Its function is to achieve highly specific recognition and regulation of target proteins. First, PROTAC Linkers need to be of sufficient length and flexibility to allow ubiquitin to successfully connect to the target protein while PROTAC binds to the target protein. The design of this flexible chain helps improve the adaptability of PROTAC to target proteins of different structures and sizes and achieve broad-spectrum protein degradation. Secondly, the chemical structure of PROTAC Linkers is crucial to the activity and stability of PROTAC. Rationally designed Linkers can affect the pharmacokinetics and pharmacodynamic properties of PROTAC molecules, thereby regulating the degradation effect of PROTAC. Linkers with specific structures can also affect the cell permeability and selectivity of PROTACs. Therefore, the design and optimization of PROTAC Linkers is crucial to achieve efficient and specific protein degradation. Such carefully designed linkers are a key component in PROTAC technology and provide important support for achieving efficient degradation of proteolytically targeted chimeras.