2. Academic Validation
  3. Potent, Selective, and Cell Active Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor Developed by Structure-Based Virtual Screening and Hit Optimization

Potent, Selective, and Cell Active Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor Developed by Structure-Based Virtual Screening and Hit Optimization

  • J Med Chem. 2017 Jul 27;60(14):6289-6304. doi: 10.1021/acs.jmedchem.7b00587.
Ruifeng Mao 1 2,  Jingwei Shao 3 4,  Kongkai Zhu 2 5,  Yuanyuan Zhang 2,  Hong Ding 2,  Chenhua Zhang 6,  Zhe Shi 6,  Hualiang Jiang 2,  Dequn Sun 1,  Wenhu Duan 3,  Cheng Luo 2 7
Affiliations

Affiliations

  • 1 Marine College, Shandong University , Weihai 264209, P.R. China.
  • 2 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS) , Shanghai 201203, China.
  • 3 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS) , Shanghai 201203, China.
  • 4 University of Chinese Academy of Sciences , Beijing 100049, China.
  • 5 School of Biological Science and Technology, University of Jinan , Jinan 250022, P.R. China.
  • 6 Shanghai ChemPartner Co., LTD. , Zhangjiang Hi-Tech Park, Shanghai 201203, China.
  • 7 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
PMID: 28650658 DOI: 10.1021/acs.jmedchem.7b00587
Abstract

PRMT5 plays important roles in diverse cellular processes and is upregulated in several human malignancies. Besides, PRMT5 has been validated as an Anticancer target in mantle cell lymphoma. In this study, we found a potent and selective PRMT5 Inhibitor by performing structure-based virtual screening and hit optimization. The identified compound 17 (IC50 = 0.33 μM) exhibited a broad selectivity against a panel of other methyltransferases. The direct binding of 17 to PRMT5 was validated by surface plasmon resonance experiments, with a Kd of 0.987 μM. Kinetic experiments indicated that 17 was a SAM competitive inhibitor other than the substrate. In addition, 17 showed selective antiproliferative effects against MV4-11 cells, and further studies indicated that the mechanism of cellular antitumor activity was due to the inhibition of PRMT5 mediated SmD3 methylation. 17 may represent a promising lead compound to understand more about PRMT5 and potentially assist the development of treatments for leukemia indications.

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