Journal of Medicinal Chemistry
Journal of Medicinal Chemistry
5 years ago

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
Dequn Sun, Hong Ding, Yuanyuan Zhang, Cheng Luo, Hualiang Jiang, Zhe Shi, Chenhua Zhang, Kongkai Zhu, Ruifeng Mao, Wenhu Duan, Jingwei Shao
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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00587

DOI: 10.1021/acs.jmedchem.7b00587

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.