2. Academic Validation
  3. Structure-Aided Design, Synthesis, and Biological Evaluation of Potent and Selective Non-Nucleoside Inhibitors Targeting Protein Arginine Methyltransferase 5

Structure-Aided Design, Synthesis, and Biological Evaluation of Potent and Selective Non-Nucleoside Inhibitors Targeting Protein Arginine Methyltransferase 5

  • J Med Chem. 2022 Jun 9;65(11):7854-7875. doi: 10.1021/acs.jmedchem.2c00398.
Deqin Rong 1,  Kaixin Zhou 2 3 4,  Wei Fang 1,  Hong Yang 3,  Yi Zhang 1,  Qiongyu Shi 3,  Yuting Huang 3 4,  Jiayi Li 3 4 5,  Hui Dong 1,  Lanlan Li 3,  Jian Ding 2 3 4 5,  Xun Huang 3 4 5 6,  Yuanxiang Wang 1
Affiliations

Affiliations

  • 1 Balance-Based Drug Discovery Laboratory, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
  • 2 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 3 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China.
  • 4 University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, P. R. China.
  • 5 Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, P. R. China.
  • 6 Lingang Laboratory, Shanghai 200031, China.
PMID: 35612488 DOI: 10.1021/acs.jmedchem.2c00398
Abstract

PRMT5 is a major type II protein arginine methyltransferase and plays important roles in diverse cellular processes. Overexpression of PRMT5 is implicated in various types of Cancer. Many efforts have been made to develop potent and selective PRMT5 inhibitors, the most potent of which is usually derived from nucleoside structures. Here, we designed a novel series of non-nucleoside PRMT5 inhibitors through the structure-aided drug design approach. SAR exploration and metabolic stability optimization led to the discovery of compound 41 as a potent PRMT5 Inhibitor with good selectivity. Additionally, compound 41 exerted antiproliferative effects against A375 cells by inducing Apoptosis and potently inhibited the methyltransferase activity of PRMT5 in cells. Moreover, it showed attractive pharmacokinetic properties and markedly suppressed the tumor growth in an A375 tumor xenograft model. These results clearly indicate that 41 is a highly potent and selective non-nucleoside PRMT5 Inhibitor.

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