國家衛生研究院 NHRI:Item 3990099045/8224
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    题名: KDM4B as a target for prostate cancer: Structural analysis and selective inhibition by a novel inhibitor
    作者: Chu, CH;Wang, LY;Hsu, KC;Chen, CC;Cheng, HH;Wang, SM;Wu, CM;Chen, TJ;Li, LT;Liu, RW;Hung, CL;Yang, JM;Kung, HJ;Wang, WC
    贡献者: Institute of Molecular and Genomic Medicine
    摘要: 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.
    日期: 2014-07
    關聯: Journal of Medicinal Chemistry. 2014 Jul;57(14):5975-5985.
    Link to: http://dx.doi.org/10.1021/jm500249n
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-2623&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000339540800011
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84905039523
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