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

• Published in: Journal of medicinal chemistry Vol. 57; no. 14; pp. 5975 - 5985
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 24.07.2014
• Subjects: Apoptosis - drug effects; Cell Proliferation - drug effects; Crystallography, X-Ray; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Jumonji Domain-Containing Histone Demethylases - antagonists & inhibitors; Jumonji Domain-Containing Histone Demethylases - chemistry; Jumonji Domain-Containing Histone Demethylases - metabolism; Kinetics; Male; Models, Molecular; Molecular Targeted Therapy; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - metabolism; Stilbenes - chemistry; Stilbenes - pharmacology; Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm500249n

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.