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

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.