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

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

85 Citations (Scopus)

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
Publication status	Published - Jul 24 2014
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/jm500249n

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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

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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}",

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doi = "10.1021/jm500249n",

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AU - Chu, Chia Han

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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

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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.

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

Abstract

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