A Novel PROTAC G9a/GLP Degrader that Inhibits, Similar to G9a siRNA, the Migration of MCF-7 Breast-Cancer Cells without Affecting Proliferation

  • J Med Chem. 2025 Sep 11;68(17):18258-18271. doi: 10.1021/acs.jmedchem.5c00704.
Anirban Mukherjee  1 ,  Yasunobu Yamashita  1 ,  Ryo Maeda  2 ,  Toshiki Akiyama  1 ,  Katsunori Endo  1 ,  Yuri Takada  1 ,  Hiroki Tsumoto  3 ,  Yukiko Moriyama  1 ,  Akihiro Ito  4 ,  Fumiyuki Shirai  5 ,  Makoto Tachibana  2 ,  Yukihiro Itoh  1  6 ,  Takayoshi Suzuki  1
Affiliations
  • 1. SANKEN, The University of Osaka, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, JAPAN.
  • 2. Laboratory of Epigenome Dynamics, Graduate School of Frontier Biosciences, The University of Osaka, 1-3 Yamadaoka, Suita, Osaka 565-0871, JAPAN.
  • 3. Proteome Research, Research Team for Mechanism of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, JAPAN.
  • 4. School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, JAPAN.
  • 5. Drug Discovery Chemistry Platform Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama, 351-0198, JAPAN.
  • 6. Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, JAPAN.
PMID: 40886138 DOI: 10.1021/acs.jmedchem.5c00704
Abstract

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 (4) based on RK-701, a less-toxic G9a/GLP-selective inhibitor. Compound 4 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 4 inhibited the migration of MCF-7 cells. These results suggest potential for 4 to serve as a valuable tool for investigating the G9a/GLP biology and as a lead compound for drug discovery.

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