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Please use this identifier to cite or link to this item:
http://ir.nhri.org.tw/handle/3990099045/8224
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| Title: | KDM4B as a target for prostate cancer: Structural analysis and selective inhibition by a novel inhibitor |
| Authors: | 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 |
| Contributors: | Institute of Molecular and Genomic Medicine |
| Abstract: | 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. |
| Date: | 2014-07 |
| Relation: | 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 |
| Appears in Collections: | [龔行健] 期刊論文
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| ISI000339540800011.pdf | | 5421Kb | Adobe PDF | 550 | View/Open |
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