2. Academic Validation
  3. Discovery of novel G9a/GLP covalent inhibitors for the treatment of triple-negative breast cancer

Discovery of novel G9a/GLP covalent inhibitors for the treatment of triple-negative breast cancer

  • Eur J Med Chem. 2023 Sep 28:261:115841. doi: 10.1016/j.ejmech.2023.115841.
Qiangsheng Zhang 1,  Bo Chang 2,  Qiang Feng 2,  Lu Li 3
Affiliations

Affiliations

  • 1 Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 17#3rd Section, Ren Min South Road, Chengdu, 610041, China.
  • 2 College of Chemistry and Life Science, Chengdu Normal University, Chengdu, 611130, PR China.
  • 3 Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Clinical Trial Center, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: lilu66@wchscu.cn.
PMID: 37788550 DOI: 10.1016/j.ejmech.2023.115841
Abstract

Triple-negative breast Cancer (TNBC) has become a serious threat to women's health. Research on epigenetic drugs is gradually deepening and is expected to provide new options for the treatment of TNBC. G9a/GLP has been shown to play an important role in the development of a variety of tumors, including TNBC. Most reported G9a/GLP inhibitors are reversible inhibitors, and covalent inhibitors with novel mechanisms of action are expected to offer unique advantages. In this study, we designed a series of novel G9a/GLP covalent inhibitors using a structure-based drug design strategy. Compound 7c (ZZM-1220) exhibited potent Enzyme inhibitory activity and anti-TNBC proliferative activity. Our biochemical studies showed that ZZM-1220 could covalently bind to G9a/GLP and inhibit H3K9me2 in cells. It could significantly induce Apoptosis of TNBC cells and block the cell cycle in the G2/M phase. It is worth noting that ZZM-1220 continuously inhibited the growth of Cancer cells and the expression of H3K9me2 after washing out. These data suggested that ZZM-1220 could be used as a promising lead compound for the development of G9a/GLP covalent inhibitors for the treatment of TNBC.

Keywords

Covalent inhibitors; G9a/GLP; Histone methylation; TNBC.

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