Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 239, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114528
Keywords
NSD3; PROTAC; Degrader; Methyltransferase
Categories
Funding
- Natural Science Foundation of Shanghai (China) [21ZR1475500]
- Young Elite Scientists Sponsorship Program by CAST (China) [2019-2021QNRC001]
- Open Program of State Key Laboratory of Drug Research (China) [SIMM2105KF-04]
- China Postdoctoral Science Foundation [2021M703353]
- Shanghai Sailing Program [22YF1457500]
- National Natural Science Foundation of China [8210130546, 21922707]
- General Program of National Natural Science Foundation of China [82173835]
- Major projects of National Natural Science Foundation of China [81991523]
- Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning (China) [2019CXJQ02]
- SA-SIBS Scholarship Program
- Shanghai Municipal Science and Technology Major Project
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This study reports the discovery of small-molecule NSD3 degraders based on the PROTAC strategy and demonstrates that inducing NSD3 degradation is a more effective approach than blocking the NSD3-PWWP domain in inhibiting NSD3 function, providing a potential therapeutic approach for lung cancer.
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.
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