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dc.contributor.authorChu, Chia-Hanen_US
dc.contributor.authorWang, Ling-Yuen_US
dc.contributor.authorHsu, Kai-Chengen_US
dc.contributor.authorChen, Chung-Chinen_US
dc.contributor.authorCheng, Hsing-Hungen_US
dc.contributor.authorWang, Szu-Minen_US
dc.contributor.authorWu, Chien-Mingen_US
dc.contributor.authorChen, Tsan-Janen_US
dc.contributor.authorLi, Ling-Tingen_US
dc.contributor.authorLiu, Ruiwuen_US
dc.contributor.authorHung, Chiu-Lienen_US
dc.contributor.authorYang, Jing-Moonen_US
dc.contributor.authorKung, Hsing-Jienen_US
dc.contributor.authorWang, Wen-Chingen_US
dc.date.accessioned2014-12-08T15:36:31Z-
dc.date.available2014-12-08T15:36:31Z-
dc.date.issued2014-07-24en_US
dc.identifier.issn0022-2623en_US
dc.identifier.urihttp://dx.doi.org/10.1021/jm500249nen_US
dc.identifier.urihttp://hdl.handle.net/11536/24866-
dc.description.abstractThe 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.en_US
dc.language.isoen_USen_US
dc.titleKDM4B as a Target for Prostate Cancer: Structural Analysis and Selective Inhibition by a Novel Inhibitoren_US
dc.typeArticleen_US
dc.identifier.doi10.1021/jm500249nen_US
dc.identifier.journalJOURNAL OF MEDICINAL CHEMISTRYen_US
dc.citation.volume57en_US
dc.citation.issue14en_US
dc.citation.spage5975en_US
dc.citation.epage5985en_US
dc.contributor.department生物資訊及系統生物研究所zh_TW
dc.contributor.departmentInstitude of Bioinformatics and Systems Biologyen_US
dc.identifier.wosnumberWOS:000339540800011-
dc.citation.woscount2-
Appears in Collections:Articles


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