KDM4B as a Target for Prostate Cancer: Structural Analysis and Selective Inhibition by a Novel Inhibitor

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：July 24, 2014
• 年：2014
• 卷：57
• 期：14
• 页码：5975-5985
• 全文大小：704K
• ISSN：1520-4804

文摘

The KDM4/JMJD2 Jumonji C-containing histone lysine demethylases (KDM4A鈥揔DM4D), 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路pyridine 2,4-dicarboxylic acid路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.