EZH2-IN-4 is a highly potent EZH2 inhibitor that can be taken orally. It exhibits inhibitory effects against wild type (WT) 5-membered (5-mer) EZH2 and mutant 5-mer EZH2, with IC 50 values of 0.923 nM and 2.65 nM, respectively. Moreover, EZH2-IN-4 has demonstrated significant anti-cancer activity.

EZH2 (mutant 5-mer):2.65 nM (IC50), EZH2 (WT 5-mer):0.923 nM (IC50)

EZH2-IN-4 (example 38) exhibits potent inhibition in Karpas-422 (EZH2 Y641N) cells with an H3K27me3 IC50 of 0.00973 nM and an IC50 of 10.1 nM in Plate Kj«pas-422 cells[1]. It suppresses the growth of various ovarian cancer cell lines (COV-434, TOV-21G, TOV-112D, A2780, Caov-3, OVCAR3), with IC50 values r ng ng from 0.02 to 8.6 μM, while show ng no inhibitory effect on SKOV3, HeyA8, and HEC59 cells (IC50 > 20 μM)[1].

'EZH2-IN-4 (example 38; oral gavage; 15 mpk; BID) shows 73% inhibition of tumor methylation in the Karpas-422 xenograft model[1]. Additionally, administered twice daily at 50 mpk orally (po) with a 5-day pretreatment, followed by at least 23 days of concurrent administration with gemcitabine and cisplatin, it significantly inhibits tumor growth in the A2780 xenograft model[1].'