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

  • J Med Chem. 2014 Jul 24;57(14):5975-85. doi: 10.1021/jm500249n.
Chia-Han Chu  1 ,  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
Affiliations
  • 1. Institute of Molecular and Cellular Biology and Department of Life Sciences and ‡Biomedical Science and Engineering Center, National Tsing-Hua University , Hsinchu, 30013, Taiwan.
PMID: 24971742 DOI: 10.1021/jm500249n
Abstract

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.

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