2. Academic Validation
  3. One stone two birds: Introducing piperazine into a series of nucleoside derivatives as potent and selective PRMT5 inhibitors

One stone two birds: Introducing piperazine into a series of nucleoside derivatives as potent and selective PRMT5 inhibitors

  • Eur J Med Chem. 2024 Oct 19:281:116970. doi: 10.1016/j.ejmech.2024.116970.
Huaxuan Li 1,  Hong Yang 2,  Li Liu 3,  Jiahong Zheng 3,  Qiongyu Shi 2,  Bang Li 3,  Xingcan Wang 4,  Ying Zhang 5,  Ruilin Zhou 6,  Jian Zhang 7,  Zhong-Zhu Chen 8,  Chang-Yun Wang 9,  Yuanxiang Wang 10,  Xun Huang 11,  Zhiqing Liu 12
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity, School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, 266237, China; Balance-Based Drug Discovery Laboratory, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
  • 2 Lingang Laboratory, Shanghai, 200031, China.
  • 3 Balance-Based Drug Discovery Laboratory, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
  • 4 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 5 Lingang Laboratory, Shanghai, 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 6 School of Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
  • 7 Thoracic Surgery Department, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
  • 8 College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing University of Arts and Sciences, Chongqing, 402160, China.
  • 9 MOE Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity, School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, 266237, China. Electronic address: changyun@ouc.edu.cn.
  • 10 Balance-Based Drug Discovery Laboratory, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China. Electronic address: wangyx95@mail.sysu.edu.cn.
  • 11 Lingang Laboratory, Shanghai, 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; School of Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China. Electronic address: xhuang@simm.ac.cn.
  • 12 MOE Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity, School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, 266237, China. Electronic address: liuzhiqing@ouc.edu.cn.
PMID: 39488968 DOI: 10.1016/j.ejmech.2024.116970
Abstract

The protein arginine methyltransferase 5 (PRMT5) has emerged as potential target for the treatment of Cancer. Many efforts have been made to develop potent and selective PRMT5 inhibitors targeting either S-adenosyl methionine (SAM) pocket or substrate binding pocket. Here, we rationally designed a series of nucleoside derivatives incorporated with piperazine as novel PRMT5 inhibitors occupying both pockets. The representative compound 36 exhibited highly potent PRMT5 inhibition activity as well as good selectivity over Other methyltransferases. Further cellular experiments revealed that compound 36 potently reduced the level of symmetric dimethylarginines (sDMA) and inhibited the proliferation of MOLM-13 cell lines by inducing Apoptosis and cell cycle arrest. Moreover, compound 36 had more favorable metabolic stability and aqueous solubility than JNJ64619178 (9). Meanwhile, it obviously suppressed the tumor growth in a MOLM-13 tumor xenograft model. These results clearly indicate that 36 is a highly potent and selective PRMT5 Inhibitor worthy for further development.

Keywords

Metabolic stability; Nucleoside derivatives; Piperazine; Protein arginine methyltransferase 5; Symmetric dimethylarginines.

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