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

Chia-Han Chu | Zendy; LingYu Wang | Zendy; KaiCheng Hsu | Zendy; Chung-Chin Chen | Zendy; Hsing-Hung Cheng | Zendy; Szu-Min Wang | Zendy; ChienMing Wu | Zendy; Tsan-Jan Chen | Zendy; Ling-Ting Li | Zendy; Ruiwu Liu | Zendy; Chiu-Lien Hung | Zendy; JinnMoon Yang | Zendy; Hsing-Jien Kung | Zendy; WenChing Wang | Zendy

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

Author(s) -

Chia-Han Chu,

LingYu Wang,

KaiCheng Hsu,

Chung-Chin Chen,

Hsing-Hung Cheng,

Szu-Min Wang,

ChienMing Wu,

Tsan-Jan Chen,

Ling-Ting Li,

Ruiwu Liu,

Chiu-Lien Hung,

JinnMoon Yang,

Hsing-Jien Kung,

WenChing Wang

Publication year - 2014

Publication title -

journal of medicinal chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.01

H-Index - 261

eISSN - 1520-4804

pISSN - 0022-2623

DOI - 10.1021/jm500249n

Subject(s) - chemistry , histone , prostate cancer , histone h3 , epigenetics , lysine , cancer research , gene silencing , biochemistry , microbiology and biotechnology , cancer , gene , biology , amino acid , genetics

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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