2. Academic Validation
  3. Identification of a novel small-molecule inhibitor of heterochromatin protein 1

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

  • Bioorg Med Chem Lett. 2026 Feb 1:131:130469. doi: 10.1016/j.bmcl.2025.130469.
Akari Tokuyama 1,  Yasunobu Yamashita 2,  Ryo Maeda 3,  Toshiki Akiyama 1,  Yuri Takada 1,  Ryunosuke Yoshino 4,  Hiroki Kato 1,  Shengwang Yu 1,  Yukihiro Itoh 5,  Makoto Tachibana 3,  Takayoshi Suzuki 6
Affiliations

Affiliations

  • 1 SANKEN, The University of Osaka, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan.
  • 2 SANKEN, The University of Osaka, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan. Electronic address: [email protected].
  • 3 Graduate School of Frontier Biosciences, The University of Osaka, Suita, Osaka 565-0871, Japan.
  • 4 Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.
  • 5 SANKEN, The University of Osaka, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan; Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
  • 6 SANKEN, The University of Osaka, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan. Electronic address: [email protected].
PMID: 41218699 DOI: 10.1016/j.bmcl.2025.130469
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.

Keywords

Chromodomain; Epigenetics; HP1; In silico screening; Protein–protein interaction.

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