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.

中文翻译：

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基于赛庚啶的新型组蛋白甲基转移酶SET7 / 9抑制剂的开发

组蛋白甲基转移酶SET7 / 9不仅将组蛋白甲基化，而且使非组蛋白蛋白质作为底物，因此，SET7 / 9抑制剂被认为是治疗疾病的候选药物。以前，我们的研究小组确定在临床上用作血清素受体拮抗剂和组胺受体（H1）拮抗剂的赛庚啶是SET7 / 9抑制剂的新型支架。在这项工作中，我们重点研究了二苯并亚戊烯作为赛庚啶的一个子结构，并合成了具有各种官能团的衍生物。其中，带有2-羟基的化合物显示出最强的活性。另一方面，3-羟基或另一个亲水性官能团（如乙酰胺）会降低活性。结构分析阐明了仅通过严格限制亲水基团的位置和类型来提高效力的理由。另外，SET7 / 9环在与赛庚啶复合物中仅部分可见，而在与2-羟基赛庚啶复合物中更清晰可见。预期这些结果将有助于SET7 / 9抑制剂的进一步基于结构的开发。