Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 57, Issue 14, Pages 5975-5985Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm500249n
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Funding
- NSC, Taiwan [NSC102-2321-B-007-003, NSC102-2325-B-007-001]
- Aim for the Top University Project of NTHU
- MOE, Taiwan, ROC
- NIH, USA
- NHRI [02A1MGPP20-014]
- MOHW, Taiwan [DOH102-TD-M-111-100001]
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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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