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) shows a cell H3K27me3 IC 50 of 0.00973 nM in Karpas-422 (EZH2 Y641N) cells[1]. EZH2-IN-4 shows an IC 50 of 10.1 nM in Plate Kj?pas-422 cells[1]. EZH2-IN-4 inhibits the proliferation of ovarian cancer cell lines (COV-434, TOV-21G, TOV-112D, A2780, Caov-3, OVCAR3; IC 50 s=0.02-8.6 μM) and has no effect on SKOV3, HeyA8, HEC59 cell (IC 50 >20 μM)[1].

EZH2-IN-4 (example 38; oral gavage; 15 mpk; BID) results in 73% inhibition of tumor methylation in the Karpas-422 xenograft model[1]. EZH2-IN-4 (po; 50 mpk; twice a day; pretreatment for 5 days; followed by co-administration with gemcitabine plus cisplatin for at least 23 additional days) significant inhibits A2780 tumor growth in A2780 xenograft model[1].