A cell-permeable GSK126 structural analog that acts as a potent, SAM-, but not substrate-, competitive inhibitor against Ezh1 and Ezh2 (IC50 = 5 and 45nM against PRC2 complex containing Ezh2 or Ezh1 in H3 peptide methylation assays; [SAM] = 5uM), while exhibiting much reduced or little potency toward panels of 15 other methyltransferases, 50 kinases, as well as 43 GPCRs, transporters, and ion channels, although high affinity binding is observed with Sigma-2 receptor S2R/PGRMC1 (Ki = 65nM) with unknown impact toward its function. Cellular H3K27me3 level is shown to be largely reduced in MCF10A, MCF7, and DB cells with no significant effect on proliferation upon a 3-day UNC1999 treatment (ICmax = 3 to 5uM), while complete cell death is reported in the EZH2 Y641N-harboring DB cell line upon an 8-day 5uM drug exposure. Both its oral bioavailability in mice and enhanced Ezh1 potency can greatly complement the Ezh2-selective GSK126 in in vitro and in vivo studies.
Primary Target:Ezh2
Secondary Target:Ezh1
Solubility:DMSO
Storage and Stability:May be stored at 4°C. For long-term storage, aliquot and store at 4°C. Do not freeze. For maximum recovery of product, centrifuge the original vial prior to removing the cap. Further dilutions can be made in assay buffer.
