Development of Novel Inhibitors for Histone Methyltransferase SET7/9 based on Cyproheptadine |
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Authors: | Dr. Tomoya Hirano Dr. Takashi Fujiwara Dr. Hideaki Niwa Michitake Hirano Kasumi Ohira Yusuke Okazaki Shin Sato Dr. Takashi Umehara Dr. Yuki Maemoto Prof. Akihiro Ito Prof. Minoru Yoshida Prof. Hiroyuki Kagechika |
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Affiliation: | 1. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Tokyo, Japan;2. Epigenetics Drug Discovery Unit, RIKEN Center for Life Science Technologies (CLST), Yokohama, Japan;3. School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan;4. Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science (CSRS), Wako, Saitama, Japan;5. Drug Discovery Platforms Cooperation Division, RIKEN Center for Sustainable Resource Science (CSRS), Wako, Saitama, Japan;6. Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan |
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Abstract: | The histone methyltransferase SET7/9 methylates not only histone but also non‐histone proteins as substrates, and therefore, SET7/9 inhibitors are considered candidates for the treatment of diseases. Previously, our group identified cyproheptadine, used clinically as a serotonin receptor antagonist and histamine receptor (H1) antagonist, as a novel scaffold of the SET7/9 inhibitor. In this work, we focused on dibenzosuberene as a substructure of cyproheptadine and synthesized derivatives with various functional groups. Among them, the compound bearing a 2‐hydroxy group showed the most potent activity. On the other hand, a 3‐hydroxy group or another hydrophilic functional group such as acetamide decreased the activity. Structural analysis clarified a rationale for the improved potency only by tightly restricted location and type of the hydrophilic group. In addition, a SET7/9 loop, which was only partially visible in the complex with cyproheptadine, became more clearly visible in the complex with 2‐hydroxycyproheptadine. These results are expected to be helpful for further structure‐based development of SET7/9 inhibitors. |
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Keywords: | cyproheptadine epigenetics histone methyltransferase inhibitors polycycles |
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