Identification of novel lysine demethylase 5-selective inhibitors by inhibitor-based fragment merging strategy |
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Authors: | Yuka Miyake Yukihiro Itoh Atsushi Hatanaka Yoshinori Suzuma Miki Suzuki Hidehiko Kodama Yoshinobu Arai Takayoshi Suzuki |
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Affiliation: | 1. Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamo-hangi-cho, Sakyo-ku, Kyoto 603-0823, Japan;2. Nippon Pharmaceutical Chemicals Co., Ltd., 2-8-18 Higashiosaka-shi, Osaka 577-0056, Japan;3. CREST, Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan |
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Abstract: | Histone lysine demethylases (KDMs) have drawn much attention as targets of therapeutic agents. KDM5 proteins, which are Fe(II)/α-ketoglutarate-dependent demethylases, are associated with oncogenesis and drug resistance in cancer cells, and KDM5-selective inhibitors are expected to be anticancer drugs. However, few cell-active KDM5 inhibitors have been reported and there is an obvious need to discover more. In this study, we pursued the identification of highly potent and cell-active KDM5-selective inhibitors. Based on the reported KDM5 inhibitors, we designed several compounds by strategically merging two fragments for competitive inhibition with α-ketoglutarate and for KDM5-selective inhibition. Among them, compounds 10 and 13, which have a 3-cyano pyrazolo[1,5-a]pyrimidin-7-one scaffold, exhibited strong KDM5-inhibitory activity and significant KDM5 selectivity. In cellular assays using human lung cancer cell line A549, 10 and 13 increased the levels of trimethylated lysine 4 on histone H3, which is a specific substrate of KDM5s, and induced growth inhibition of A549 cells. These results should provide a basis for the development of cell-active KDM5 inhibitors to highlight the validity of our inhibitor-based fragment merging strategy. |
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Keywords: | JHDM KDM Histone methylation Epigenetics Inhibitor design |
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