SKLB03220

SKLB03220 is a covalent inhibitor of the histone-lysine methyltransferase enhancer of zeste homolog 2 (EZH2, IC50 = 1.72 nM). It also inhibits EZH2A677G, EZH2Y641N, and EZH2Y641F, mutations found in various cancers, when used at a concentration of 10 nM. SKLB03220 is selective for EZH2 over a variety of other histone-lysine methyltransferases, including G9a, SUV39H1, SET domain-containing protein 8 (SETD8), SMYD2, and protein arginine methyltransferase 1-7 (PRMT1-7) at 10 µM but does inhibit EZH1 at 1 and 10 µM. It is also selective for EZH2 over a panel of 224 kinases at 200 nM. SKLB03220 inhibits the proliferation of PA-1 and A2780 ovarian cancer cells in a concentration-dependent manner. It reduces levels of trimethylated histone H3 lysine 27 (H3K27Me3) and induces apoptosis in PA-1 cells. SKLB03220 (75 and 150 mg/kg twice per day) reduces tumor growth in a PA-1 mouse xenograft model.. SMILES: O=C(NC1=CC=C(C)C(C2=CC(N(CC)C3CCOCC3)=C(C(C(NCC4=C(C=C(NC4=O)C)C)=O)=C2)C)=C1)C=C. InChi Code: InChI=1S/C33H40N4O4/c1-7-31(38)36-25-10-9-20(3)27(18-25)24-16-28(32(39)34-19-29-21(4)15-22(5)35-33(29)40)23(6)30(17-24)37(8-2)26-11-13-41-14-12-26/h7,9-10,15-18,26H,1,8,11-14,19H2,2-6H3,(H,34,39)(H,35,40)(H,36,38). InChi Key: QKOGMESAENVJHH-UHFFFAOYSA-N