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

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

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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