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

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.