KDM4B as a target for prostate cancer: Structural analysis and selective inhibition by a novel inhibitor

Chia Han Chu; Ling Yu Wang; Kai Cheng Hsu; Chung Chin Chen; Hsing Hung Cheng; Szu Min Wang; Chien Ming Wu; Tsan Jan Chen; Ling Ting Li; Ruiwu Liu; Chiu Lien Hung; Jing Moon Yang; Hsing Jien Kung; Wen Ching Wang

doi:10.1021/jm500249n

KDM4B as a target for prostate cancer: Structural analysis and selective inhibition by a novel inhibitor

Chia Han Chu
, Ling Yu Wang
, Kai Cheng Hsu
, Chung Chin Chen
, Hsing Hung Cheng
, Szu Min Wang
, Chien Ming Wu
, Tsan Jan Chen
, Ling Ting Li
, Ruiwu Liu
, Chiu Lien Hung
, Jing Moon Yang^*
, Hsing Jien Kung
, Wen Ching Wang

^*Corresponding author for this work

Research output: Contribution to journal › Journal Article › peer-review

91 Scopus citations

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.

Original language	English
Pages (from-to)	5975-5985
Number of pages	11
Journal	Journal of Medicinal Chemistry
Volume	57
Issue number	14
DOIs	https://doi.org/10.1021/jm500249n
State	Published - 24 07 2014
Externally published	Yes

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Chu, C. H., Wang, L. Y., Hsu, K. C., Chen, C. C., Cheng, H. H., Wang, S. M., Wu, C. M., Chen, T. J., Li, L. T., Liu, R., Hung, C. L., Yang, J. M., Kung, H. J., & Wang, W. C. (2014). KDM4B as a target for prostate cancer: Structural analysis and selective inhibition by a novel inhibitor. Journal of Medicinal Chemistry, 57(14), 5975-5985. https://doi.org/10.1021/jm500249n

@article{0cee9640a85444e9b212035ef27d0379,

title = "KDM4B as a target for prostate cancer: Structural analysis and selective inhibition by a novel inhibitor",

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.",

author = "Chu, \{Chia Han\} and Wang, \{Ling Yu\} and Hsu, \{Kai Cheng\} and Chen, \{Chung Chin\} and Cheng, \{Hsing Hung\} and Wang, \{Szu Min\} and Wu, \{Chien Ming\} and Chen, \{Tsan Jan\} and Li, \{Ling Ting\} and Ruiwu Liu and Hung, \{Chiu Lien\} and Yang, \{Jing Moon\} and Kung, \{Hsing Jien\} and Wang, \{Wen Ching\}",

year = "2014",

month = jul,

day = "24",

doi = "10.1021/jm500249n",

language = "英语",

volume = "57",

pages = "5975--5985",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "14",

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TY - JOUR

T1 - KDM4B as a target for prostate cancer

T2 - Structural analysis and selective inhibition by a novel inhibitor

AU - Chu, Chia Han

AU - Wang, Ling Yu

AU - Hsu, Kai Cheng

AU - Chen, Chung Chin

AU - Cheng, Hsing Hung

AU - Wang, Szu Min

AU - Wu, Chien Ming

AU - Chen, Tsan Jan

AU - Li, Ling Ting

AU - Liu, Ruiwu

AU - Hung, Chiu Lien

AU - Yang, Jing Moon

AU - Kung, Hsing Jien

AU - Wang, Wen Ching

PY - 2014/7/24

Y1 - 2014/7/24

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84905039523

U2 - 10.1021/jm500249n

DO - 10.1021/jm500249n

M3 - 文章

C2 - 24971742

AN - SCOPUS:84905039523

SN - 0022-2623

VL - 57

SP - 5975

EP - 5985

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 14

ER -

KDM4B as a target for prostate cancer: Structural analysis and selective inhibition by a novel inhibitor

Abstract

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