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
  • 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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