A Novel PROTAC G9a/GLP Degrader that Inhibits, Similar to G9a siRNA, the Migration of MCF-7 Breast-Cancer Cells without Affecting Proliferation
G9a and G9a-like protein (GLP) are histone methyltransferases that regulate epigenetics by adding methyl groups to histone H3, thereby controlling gene expression. G9a/GLP dysregulation and overexpression have been reported to cause cancer proliferation, progression, and metastasis. So far, quinazoline-based inhibitors and degraders have been frequently used as chemical tools to elucidate the role of G9a/GLP. However, quinazoline-based inhibitors exhibit toxicity in normal cells. In this context, we identified a G9a/GLP degrader (<b>4</b>) based on RK-701, a less-toxic G9a/GLP-selective inhibitor. Compound <b>4</b> effectively decreased G9a/GLP protein levels and methylated histone levels in breast cancer MCF-7 cells without inhibiting the cell viability, similar to G9a small interfering RNA (siRNA). Furthermore, again similar to G9a siRNA, the degradation of G9a/GLP by <b>4</b> inhibited the migration of MCF-7 cells. These results suggest potential for <b>4</b> to serve as a valuable tool for investigating the G9a/GLP biology and as a lead compound for drug discovery.
Authors
- Yuri Takada (ORCID: https://orcid.org/0000-0002-7955-6567)
- Yasunobu Yamashita (ORCID: https://orcid.org/0000-0001-5078-5940)
- Yukiko Moriyama
- Hiroki Tsumoto (ORCID: https://orcid.org/0009-0002-9717-739X)
- Makoto Tachibana (ORCID: https://orcid.org/0000-0001-7977-1120)
- Ryo Maeda (ORCID: https://orcid.org/0000-0003-3302-7392)
- Takayoshi Suzuki (ORCID: https://orcid.org/0000-0003-2439-879X)
- Anirban Mukherjee (ORCID: https://orcid.org/0000-0001-7083-7322)
- Yukihiro Itoh (ORCID: https://orcid.org/0000-0002-3410-2924)
- Fumiyuki Shirai (ORCID: https://orcid.org/0000-0003-0593-2467)
- Toshiki Akiyama (ORCID: https://orcid.org/0000-0003-4410-7646)
- Akihiro Ito (ORCID: https://orcid.org/0000-0003-0908-8929)
- Katsunori Endo
Institutions
- Tokyo University of Pharmacy and Life Sciences (JP)
- BC Platforms (Finland) (FI)
- RIKEN Center for Sustainable Resource Science (JP)
- Drug Discovery Laboratory (Norway) (NO)
- Tokyo Metropolitan Institute of Gerontology (JP)
- Japan Space Forum (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-08-31
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00704
- Citations
- 1
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Japan Agency for Medical Research and Development
- Japan Society for the Promotion of Science