1. Development of Novel Inhibitors for Histone Methyltransferase SET7/9 based on Cyproheptadine.
- Author
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Hirano T, Fujiwara T, Niwa H, Hirano M, Ohira K, Okazaki Y, Sato S, Umehara T, Maemoto Y, Ito A, Yoshida M, and Kagechika H
- Subjects
- Crystallography, X-Ray, Enzyme Inhibitors chemistry, Humans, Hydrophobic and Hydrophilic Interactions, Protein Conformation, Cyproheptadine chemistry, Cyproheptadine pharmacology, Enzyme Inhibitors pharmacology, Histone-Lysine N-Methyltransferase antagonists & inhibitors
- 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., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2018
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