EZH2 inhibitor C36 is a potent, selective and allosteric EZH2-PRC2 inhibitor with IC50 of 2.27 nM in AlphaLisa assays, inhibits both the basal and activated forms of the PRC2 complex containing EZH2, but not EZH1, in a SAM-noncompetitive manner.
C36 inhibits the methyltransferase activity of PRC2 and PRC2-JARID2 with IC50 values of 121 and 66 nM, respectively.
C36 binds to a pocket at the interface of SET-Activation-Loop (SAL), stimulation-responsive motif (SRM), and I-SET domain of EZH2, and WD40 domain of EED.
C36 binding induces conformational changes and disrupts allosteric communication between EZH2 and ligand-bound EED.
EZH2 inhibitor C36 greatly reduced H3K27me3 in DLBCL cell lines harboring EZH2 wild-type (Toledo, OCI-ly19, SU-DHL-1) or GOF mutants (WSU-DLCL2, SU-DHL-4, Karpas422 Pfeiffer).
C36 efficiently inhibits H3K27 trimethylation and PRC2 target gene expression in tumor cells and xenograft tumors with low hematotoxicity.