Discovery of Dual Lysine Methyltransferase G9a and EZH2 Inhibitors with In Vivo Efficacy against Malignant Rhabdoid Tumor

In recent years, it has been proposed that G9a/EZH2 dual inhibition is a promising cancer treatment strategy. Herein, we present the discovery of G9a/EZH2 dual inhibitors that merge the pharmacophores of G9a and EZH2 inhibitors. Among them, the most promising compound 15h displayed potent inhibitory activities against G9a (IC₅₀ = 2.90 ± 0.05 nM) and EZH2 (IC₅₀ = 4.35 ± 0.02 nM), superior antiproliferative profiles against RD (CC₅₀ = 19.63 ± 0.18 μM) and SW982 (CC₅₀ = 19.91 ± 0.50 μM) cell lines. In vivo, 15h achieved significant antitumor efficacy in a xenograft mouse model of human rhabdoid tumor with a tumor growth inhibitory rate of 86.6% without causing observable toxic effects. The on-target activity assays illustrated that compound 15h can inhibit tumor growth by specifically inhibiting EZH2 and G9a. Therefore, 15h is a potential anticancer drug candidate for the treatment of malignant rhabdoid tumor.