Design and discovery of new pyrimidine coupled nitrogen aromatic rings as chelating groups of JMJD3 inhibitors

Jianping Hu, Xin Wang, Lin Chen, Min Huang, Wei Tang, Jianping Zuo, Yu Chih Liu, Zhe Shi, Rongfeng Liu, Jingkang Shen, Bing Xiong

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


The histone methylation on lysine residues is one of the most studied post-translational modifications, and its aberrant states have been associated with many human diseases. In 2012, Kruidenier et al. reported GSK-J1 as a selective Jumonji H3K27 demethylase (JMJD3 and UTX) inhibitor. However, there is limited information on the structure-activity relationship of this series of compounds. Moreover, there are few scaffolds reported as chelating groups for Fe(II) ion in Jumonji demethylase inhibitors development. To further elaborate the structure-activity relationship of selective JMJD3 inhibitors and to explore the novel chelating groups for Fe(II) ion, we initialized a medicinal chemistry modification based on the GSK-J1 structure. Finally, we found that several compounds bearing different chelating groups showed similar activities with respect to GSK-J1 and excellent metabolic stability in liver microsomes. The ethyl ester prodrugs of these inhibitors also showed a better activity than GSK-J4 for inhibition of TNF-α production in LPS-stimulated murine macrophage cell line Raw 264.7 cells. Taking together, the current study not only discovered alternative potent JMJD3 inhibitors, but also can benefit other researchers to design new series of Jumonji demethylase inhibitors based on the identified chelating groups.

Original languageEnglish
Pages (from-to)721-725
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Issue number3
StatePublished - 2016
Externally publishedYes


  • Chelating group
  • Epigenetics
  • GSK-J1
  • Histone demethylase
  • JMJD3 inhibitors


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