Background:

UNC1999 is an orally bioavailable inhibitor of EZH2 and EZH1 with IC50 values of [1].

UNC1999 binds to the EZH2 SAM binding site of EZH2 and competes with the cofactor SAM with a Ki of 4.6nM. It does not compete with the H3 peptide substrate. UNC1999 also has potency for mutant EZH2, including Y641N and Y641F mutants. Besides EZH2, UNC1999 is effective for EZH1 with IC50 value of 45nM. UNC1999 is shown to be more than 200-fold selective for EZH2 over a broad range of non-epigenetic targets, including kinases, GPCRs, transporters and ion channels [1].

EZH2 catalyzes methylation of H3K27, producing H3K27me3. H3K27me3 is a transcriptionally repressive post-translational modification. As an inhibitor of EZH2, UNC1999 reduces H3K27me3 with IC50 value of 124nM in the In-Cell Western assay. Additionally, UNC1999 can inhibit cell proliferation in a DLBCL cell line harboring the Y641N mutant with EC50 value of 633nM. Moreover, UNC1999 is reported to be orally bioavailable in mice [1].

参考文献:
[1] Konze KD, Ma A, Li F, Barsyte-Lovejoy D, Parton T, Macnevin CJ, Liu F, Gao C, Huang XP, Kuznetsova E, Rougie M, Jiang A, Pattenden SG, Norris JL, James LI, Roth BL, Brown PJ, Frye SV, Arrowsmith CH, Hahn KM, Wang GG, Vedadi M, Jin J. An orally bioavailable chemical probe of the Lysine Methyltransferases EZH2 and EZH1. ACS Chem Biol. 2013;8(6):1324-34.