2. Academic Validation
  3. Discovery of a potent and selective proteolysis targeting chimera (PROTAC) degrader of NSD3 histone methyltransferase

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

  • Eur J Med Chem. 2022 Sep 5:239:114528. doi: 10.1016/j.ejmech.2022.114528.
Yaoliang Sun 1,  Ying Zhang 2,  Xiaoai Chen 3,  Aisong Yu 2,  Wenhao Du 3,  Yuting Huang 2,  Feifei Wu 4,  Lei Yu 5,  Jiayi Li 6,  Cuiyun Wen 1,  Hong Yang 7,  Qiongyu Shi 7,  Meiyu Geng 8,  Xun Huang 9,  Shilin Xu 10
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Qixia District, Nanjing, 210023, PR China.
  • 4 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; University of Chinese Academy of Sciences, NO. 19A Yuquan Road, Beijing, 100049, PR China.
  • 5 Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
  • 6 Hangzhou Institute for Advanced Study, UCAS, Hangzhou, 310024, PR China.
  • 7 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; Lingang Laboratory, Shanghai, 200210, PR China.
  • 8 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; Hangzhou Institute for Advanced Study, UCAS, Hangzhou, 310024, PR China. Electronic address: [email protected].
  • 9 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; Hangzhou Institute for Advanced Study, UCAS, Hangzhou, 310024, PR China; Lingang Laboratory, Shanghai, 200210, PR China. Electronic address: [email protected].
  • 10 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; University of Chinese Academy of Sciences, NO. 19A Yuquan Road, Beijing, 100049, PR China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Qixia District, Nanjing, 210023, PR China. Electronic address: [email protected].
PMID: 35717870 DOI: 10.1016/j.ejmech.2022.114528
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 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.

Keywords

Degrader; Methyltransferase; NSD3; PROTAC.

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