2. Academic Validation
  3. Structure-based discovery of a new series of nucleoside-derived ring-opening PRMT5 inhibitors

Structure-based discovery of a new series of nucleoside-derived ring-opening PRMT5 inhibitors

  • Eur J Med Chem. 2024 Jan 28:267:116171. doi: 10.1016/j.ejmech.2024.116171.
Yuting Chen 1,  Zekun Wang 2,  Junjie Zhang 1,  Qiongyu Shi 3,  Hong Yang 3,  Yue Deng 2,  Xingcan Wang 2,  Tongchao Liu 4,  Meiyu Geng 2,  Bing Xiong 5,  Xun Huang 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 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, Beijing, 100049, PR China.
  • 3 Lingang Laboratory, Shanghai, 200031, PR China.
  • 4 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China. Electronic address: [email protected].
  • 5 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China. Electronic address: [email protected].
  • 6 University of Chinese Academy of Sciences, Beijing, 100049, PR China; Lingang Laboratory, Shanghai, 200031, PR China; Hangzhou Institute for Advanced Study, UCAS, Hangzhou, 310024, PR China. Electronic address: [email protected].
PMID: 38301329 DOI: 10.1016/j.ejmech.2024.116171
Abstract

The ubiquitous methyltransferases employing SAM as the methyl donor have emerged as potential targets in many disease treatments, especially in Anticancer. Therefore, developing SAM-competitive inhibitors of methyltransferases is of great interest to the drug research. To explore this direction, herein, we rationally designed a series of nucleoside derivatives as potent PRMT5 inhibitors with novel scaffold. The representative compounds A2 and A8 exhibited highly potent PRMT5 inhibition activity as well as good selectivity over other PRMTs and PKMTs. Further cellular experiments revealed that compounds A2 and A8 potently reduced the level of sDMA and inhibited the proliferation of Z-138 and MOLM-13 cell lines by inducing Apoptosis. Moreover, compounds A8 which had favorable pharmacokinetic properties exhibited potent antitumor efficacy without the loss of body weight in a subcutaneous MOLM-13 xenograft model. In summary, our efforts provided a series of novel nucleoside analogs as potent PRMT5 inhibitors and may also offer a new strategy to develop SAM analogs as other methyltransferases' inhibitors.

Keywords

Methyltransferases; Nucleoside derivatives; PRMT5; Structure-activity relationship.

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