Identification of a novel small-molecule inhibitor of heterochromatin protein 1

IF 2.3 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-02-01 Epub Date: 2025-11-09 DOI:10.1016/j.bmcl.2025.130469

Akari Tokuyama , Yasunobu Yamashita , Ryo Maeda , Toshiki Akiyama , Yuri Takada , Ryunosuke Yoshino , Hiroki Kato , Shengwang Yu , Yukihiro Itoh , Makoto Tachibana , Takayoshi Suzuki

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引用次数: 0

Abstract

Heterochromatin protein 1 (HP1), one of the epigenetic “reader” proteins, recognizes trimethylated lysine 9 of histone H3 (H3K9me3) to repressively regulate gene transcription by promoting chromatin aggregation. Overexpression of HP1 plays a role in the growth of various cancer cells. Therefore, inhibiting its interaction with H3K9me3 is considered a promising therapeutic strategy for cancer treatment. This study aimed to identify small molecules that bind to HP1 and inhibit the HP1/H3K9me3 interaction. We performed in silico screening of the compounds from the Osaka University Library and selected 61 virtual hit compounds. As a result of in vitro evaluation of the hits by an HP1/H3K9me3 interaction inhibition assay, we identified compound 1, which exhibited 36 % inhibitory activity at 100 μM. Furthermore, the structural optimization of 1 led to the identification of (R)-18 (IC₅₀: 18.1 μM)—a novel small molecule that inhibits the HP1/H3K9me3 interaction.

Abstract Image

查看原文本刊更多论文

一种新型异染色质蛋白小分子抑制剂的鉴定。

异染色质蛋白1 （Heterochromatin protein 1, HP1）是一种表观遗传“阅读器”蛋白，它识别组蛋白H3 （H3K9me3）的三甲基化赖氨酸9，通过促进染色质聚集来抑制基因转录。HP1的过表达在多种癌细胞的生长中起作用。因此，抑制其与H3K9me3的相互作用被认为是一种很有前景的癌症治疗策略。本研究旨在鉴定与HP1结合并抑制HP1/H3K9me3相互作用的小分子。我们对来自大阪大学图书馆的化合物进行了计算机筛选，并选择了61个虚拟命中化合物。通过体外HP1/H3K9me3相互作用抑制实验，我们鉴定出化合物1，在100 μM下具有36% %的抑制活性。此外，通过对1的结构优化，鉴定出抑制HP1/H3K9me3相互作用的新型小分子(R)-18 （IC50: 18.1 μM）。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.