KDM4B as a target for prostate cancer: Structural analysis and selective inhibition by a novel inhibitor

Chia Han Chu, Ling Yu Wang, Kai Cheng Hsu, Chung Chin Chen, Hsing Hung Cheng, Szu Min Wang, Chien Ming Wu, Tsan Jan Chen, Ling Ting Li, Ruiwu Liu, Chiu Lien Hung, Jing Moon Yang, Hsing Jien Kung, Wen Ching Wang

Research output: Contribution to journalArticlepeer-review

78 Citations (Scopus)


The KDM4/JMJD2 Jumonji C-containing histone lysine demethylases (KDM4A-KDM4D), which selectively remove the methyl group(s) from tri/dimethylated lysine 9/36 of H3, modulate transcriptional activation and genome stability. The overexpression of KDM4A/KDM4B in prostate cancer and their association with androgen receptor suggest that KDM4A/KDM4B are potential progression factors for prostate cancer. Here, we report the crystal structure of the KDM4B·pyridine 2,4-dicarboxylic acid·H3K9me3 ternary complex, revealing the core active-site region and a selective K9/K36 site. A selective KDM4A/KDM4B inhibitor, 4, that occupies three subsites in the binding pocket is identified by virtual screening. Pharmacological and genetic inhibition of KDM4A/KDM4B significantly blocks the viability of cultured prostate cancer cells, which is accompanied by increased H3K9me3 staining and transcriptional silencing of growth-related genes. Significantly, a substantial portion of differentially expressed genes are AR-responsive, consistent with the roles of KDM4s as critical AR activators. Our results point to KDM4 as a useful therapeutic target and identify a new inhibitor scaffold.

Original languageEnglish
Pages (from-to)5975-5985
Number of pages11
JournalJournal of Medicinal Chemistry
Issue number14
Publication statusPublished - Jul 24 2014
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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