標題: KDM4B as a Target for Prostate Cancer: Structural Analysis and Selective Inhibition by a Novel Inhibitor
作者: Chu, Chia-Han
Wang, Ling-Yu
Hsu, Kai-Cheng
Chen, Chung-Chin
Cheng, Hsing-Hung
Wang, Szu-Min
Wu, Chien-Ming
Chen, Tsan-Jan
Li, Ling-Ting
Liu, Ruiwu
Hung, Chiu-Lien
Yang, Jing-Moon
Kung, Hsing-Jien
Wang, Wen-Ching
生物資訊及系統生物研究所
Institude of Bioinformatics and Systems Biology
公開日期: 24-Jul-2014
摘要: 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.
URI: http://dx.doi.org/10.1021/jm500249n
http://hdl.handle.net/11536/24866
ISSN: 0022-2623
DOI: 10.1021/jm500249n
期刊: JOURNAL OF MEDICINAL CHEMISTRY
Volume: 57
Issue: 14
起始頁: 5975
結束頁: 5985
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