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Development of Novel Inhibitors for Histone Methyltransferase SET7/9 based on Cyproheptadine
Author(s) -
Hirano Tomoya,
Fujiwara Takashi,
Niwa Hideaki,
Hirano Michitake,
Ohira Kasumi,
Okazaki Yusuke,
Sato Shin,
Umehara Takashi,
Maemoto Yuki,
Ito Akihiro,
Yoshida Minoru,
Kagechika Hiroyuki
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800233
Subject(s) - cyproheptadine , methyltransferase , histone , chemistry , pharmacology , histone methyltransferase , biochemistry , biology , dna , methylation , receptor , serotonin
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.