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Description

A cell-permeable indolocarboxamide compound that acts as a potent and selective inhibitor against Ezh2/PRC2 (Polycomb repressive complex 2, Ezh2/SUZ12/EED/AEBP2/RbAP48) HMTase activity (IC50/substrate = 15 nM/H3K27me021-44 and 13 nM/H3K27me221-44, respectively, against human wt or Y641F Ezh2-containing PRC2, [SAM] = 1 microM) in a cofactor SAM-competitive manner, while inhibiting Ezh1/PRC2 only at much higher concentrations (IC50 = 1.34 microM) and exhibiting no potency toward CARM 1, Dot1L, G9a, MLL, NSD3, Set7/9, SETD2, SETD8, SmyD2, or Suv39H2 (IC50 >100 microM). Shown to suppress cellular H3K27 dimethylation and trimethylation (1 to 10 microM) in DLBCL cultures and exhibit antiproliferation activity against DLBCL cell lines with wt or mutant Ezh2 (3.3 microM to 10 microM).Please note that the molecular weight for this compound is batch-specific due to variable water content. Please refer to the vial label or the certificate of analysis for the batch-specific molecular weight. The molecular weight provided represents the baseline molecular weight without water., A cell-permeable indolocarboxamide compound that acts as a potent and selective inhibitor against Ezh2/PRC2 (Polycomb repressive complex 2, Ezh2/SUZ12/EED/AEBP2/RbAP48) HMTase activity (IC50/substrate = 15 nM/H3K27me021-44 and 13 nM/H3K27me221-44, respectively, against human wt or Y641F Ezh2-containing PRC2, [SAM] = 1 microM) in a cofactor SAM-competitive manner, while inhibiting Ezh1/PRC2 only at much higher concentrations (IC50 = 1.34 microM) and exhibiting no potency toward CARM 1, Dot1L, G9a, MLL, NSD3, Set7/9, SETD2, SETD8, SmyD2, or Suv39H2 (IC50 >,100 microM). Shown to selectively suppress cellular H3K27 dimethylation and trimethylation (1 to 10 microM in 1 to 5 days) in DLBCL (diffuse large B cell lymphoma) cultures, but not those of H3K4, H3K9, H3K36, or H3K79. EI1 is shown to exhibit antiproliferation activity against DLBCL cell lines with wt- (by 90% in G401 with 3.3 microM EI1, by 78% in Toledo with 10 microM EI1, 14 d incubation) or mutant- Ezh2 (by >96% in WSU-DLCL2/Y641F, SU-DHL6/Y641N, Karpas422/Y641N, and DB/Y641N cultures with 3.3 microM EI1, by >96% in SU-DHL4 cultures with10 microM EI1, 14 d incubation), while being less effective against MEF (by 40% in 11 days at 3.3 microM) and ineffective toward wt Ezh2-expressing GA10 and OCI-LY19.