Identification of Jumonji AT-Rich Interactive Domain 1A Inhibitors and Their Effect on Cancer Cells
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- Yukihiro Itoh
- Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto 606-0823, Japan
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- Hideyuki Sawada
- Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto 606-0823, Japan
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- Miki Suzuki
- Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto 606-0823, Japan
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- Toshifumi Tojo
- Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto 606-0823, Japan
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- Ryuzo Sasaki
- Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology, 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan
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- Makoto Hasegawa
- Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology, 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan
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- Tamio Mizukami
- Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology, 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan
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- Takayoshi Suzuki
- Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto 606-0823, Japan
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説明
Jumonji AT-rich interactive domain 1A (JARID1A), one of the jumonji C domain-containing histone demethylase (JHDM) family members, plays key roles in cancer cell proliferation and development of drug tolerance. Therefore, selective JARID1A inhibitors are potential anticancer agents. In this study, we searched for cell-active JARID1A inhibitors by screening hydroxamate compounds in our in-house library and the structural optimization based on docking study of the hit-compound to a homology model of JARID1A. As a result, we identified compound 6j, which selectively inhibits JARID1A over three other JHDM family members. Compound 7j, a prodrug form of compound 6j, induced a selective increase in the level of trimethylation of histone H3 lysine 4, a substrate of JARID1A. Furthermore, compound 7j synergistically enhanced A549 human lung cancer cell growth inhibition induced by vorinostat, a histone deacetylase inhibitor. These findings support the idea that JARID1A inhibitors have potential as anticancer agents.
収録刊行物
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- ACS Medicinal Chemistry Letters
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ACS Medicinal Chemistry Letters 6 (6), 665-670, 2015-04-28
American Chemical Society (ACS)