SKLB-03220 (SKLB03220) is a potent, selective EZH2 covalent inhibitor with IC50 of 1.72 nM (EZH2 WT).
SKLB-03220 binds the same location as the EPZ-6438, and forms a covalent bond with Cys663.
SKLB-03220 (10 nM) showed good inhibitory activity against EZH2 mutants (EZH2 A677G, EZH2 Y641N, and EZH2 Y641F).
SKLB-03220 does not exhibit inhibitory activity against other HMTases at 10 uM (G9a, SUV39H1, SETD8, SMYD2, PRMT1, PRMT5, and PRMT7), as well as a panel of 224 kinases by Eurofins Kinase Profiler.
SKLB-03220 exhibited more potent proliferation inhibitory activity than reference compounds GSK126 and EPZ-6438, especially in human ovarian cancer cell lines.
SKLB-03220 inhibited proliferation of ovarian cancer cell lines PA-1 and A2780 with IC50 of 10.1 and 11.2 uM, respectively, induced ovarian cancer cell apoptosis in a dose-dependent manner, inhibited the expression of H3K27me3 in ovarian cancer cells.
SKLB-03220 (150 mg/kg, oral, twice daily) reduced the tumor growth in PA-1 tumor xenograft model in BALB/c nude mice, exhibited greater tumor growth inhibition (TGI) than EPZ-6438 (150 mg/kg) group.