Design, synthesis and evaluation of EZH2-based PROTACs targeting PRC2 complex in lymphoma

The novel EZH2 degrading agent E-3P-MDM2 induced robust cell viability inhibition in both HBL-1 (EZH2WT) and SU-DHL-6 (EZH2Y614N), which was much stronger than that of EPZ6438. E-3P-MDM2 can effectively degrade EZH2 of SU-DHL-6 cells in a concentration and dose-dependent manner, degrading EED and SUZ12 proteins at the same time, and then significantly inhibiting the expression of H3K27me3. Furthermore, E-3P-MDM2 can intervene in the cell growth of SU-DHL-6 by inducing apoptosis. [Display omitted] •EZH2 degrading agent was synthesized for VHL, CRBN, MDM2 or cIAP E3 ligase system.•E-3P-MDM2 can effectively degrade EZH2 in SU-DHL-6 cells.•E-3P-MDM2 induces apoptosis in SU-DHL-6 cells via mitochondrial pathway. EZH2 is a member of PcG and can induce the occurrence of cancer when it is highly expressed. As an EZH2 inhibitor, Tazemetostat (EPZ6438) can inhibit the methylation catalytic activity of EZH2. However, many studies have shown that inhibition of EZH2 alone does not efficiently block tumor development. Therefore, in this study, proteolytic targeting chimera technology was employed to enhance the antiproliferative potency of EPZ6438 by degrading the oncogenic activity of EZH2. Several PROTACs have been synthesized by combining EPZ6438 with four E3 ligase ligands based on VHL, CRBN, MDM2, and cIAP E3 ligase systems. In our study, compound E-3P-MDM2 is the most active PROTAC molecule. It degraded EZH2 of the SU-DHL-6 cells in a concentration and dose-dependent manner and also degraded both EED and SUZ12 protein without affecting their mRNA levels, then significantly inhibited the expression of H3K27me3. The in vitro antiproliferative activity of E-3P-MDM2 was much stronger than that of EPZ6438.