2. Academic Validation
  3. Discovery of 2,4-diphenyl-substituted thiazole derivatives as PRMT1 inhibitors and investigation of their anti-cervical cancer effects

Discovery of 2,4-diphenyl-substituted thiazole derivatives as PRMT1 inhibitors and investigation of their anti-cervical cancer effects

  • Bioorg Med Chem. 2023 Jul 30;92:117436. doi: 10.1016/j.bmc.2023.117436.
Ziqi Zhao 1,  Jungan Zhang 1,  Yixin Ren 2,  Luyao Dong 3,  Han Wu 1,  Wei Hong 4,  Huoqiang Huang 1,  Xinyi Yang 5,  Zongran Pang 6,  Hao Wang 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Minzu University of China, Beijing 100081, PR China; Key Laboratory of Ethnomedicine (MinZu University of China), Ministry of Education, Beijing 100081, PR China.
  • 2 Institute of National Security, Minzu University of China, Beijing 100081, PR China.
  • 3 Beijing Key Laboratory of Antimicrobial Agents/Laboratory of Pharmacology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
  • 4 Jingjinji National Center of Technology Innovation, Beijing 100094, PR China.
  • 5 Beijing Key Laboratory of Antimicrobial Agents/Laboratory of Pharmacology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China. Electronic address: xinyiyang@imb.cams.cn.
  • 6 School of Pharmacy, Minzu University of China, Beijing 100081, PR China; Key Laboratory of Ethnomedicine (MinZu University of China), Ministry of Education, Beijing 100081, PR China. Electronic address: pangzongran@muc.edu.cn.
  • 7 School of Pharmacy, Minzu University of China, Beijing 100081, PR China; Key Laboratory of Ethnomedicine (MinZu University of China), Ministry of Education, Beijing 100081, PR China; Institute of National Security, Minzu University of China, Beijing 100081, PR China. Electronic address: hao.wang@muc.edu.cn.
PMID: 37556911 DOI: 10.1016/j.bmc.2023.117436
Abstract

Cervical Cancer is one of the most common cancers that affects middle-aged women and the discovery of new drugs to aid clinical management is needed. As an important member of the protein arginine methyltransferases (PRMTs) family, PRMT1 catalyzes the methylation of protein arginine, which can influence multiple biological processes of Cancer cells, such as activating epithelial-mesenchymal transformation (EMT) and acquiring resistance to Apoptosis. Therefore, PRMT1 can be considered as a potential drug target for cervical Cancer. In the current study, a new sub-binding pocket was discovered by molecular modeling, and by introducing a third substitute on the thiazole group to occupy this pocket, a series of compounds were designed and synthesized as potential PRMT1 inhibitors. Of these, two compounds (ZJG51 and ZJG58) exhibited significant inhibitory activities against PRMT1 without significantly inhibiting PRMT5. Both ZJG51 and ZJG58 displayed potent inhibitory effects on the proliferation of four cancer-derived cell lines and ZJG51 exerted relative selectivity against the cervical Cancer cell line, HeLa. Further studies showed that ZJG51 inhibited migration and induce the Apoptosis of HeLa cells. Mechanistically, ZJG51 significantly regulated PRMT1 related proteins, and indicated that the induction of Apoptosis and inhibition of migration by ZJG51 may involve the activation of Caspase 9 and the inhibition of EMT, respectively. Molecular dynamic simulation and free energy calculation showed that ZJG51 can bind to PRMT1 stably and the binding mode was predicted. These data indicated that introducing the third substitute on the five-membered ring could be a future direction for structure-based optimization of PRMT1 inhibitors, and ZJG51 could be an important lead compound to inform the design of more potent inhibitors.

Keywords

Drug design; EMT; Inhibitors; Molecular modeling; PRMT1.

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