Description
EZH2 is a histone methyltransferase and its activation leads to alteration in cell cycle regulation, proliferation, and cancer progression [65]. High expression and mutation of EZH2 are in a variety of malignancies and usually portend for
a poor prognosis.
Uses
EI1 (KB-145943) is a potent and selectiveEZH2inhibitor withIC50of 15 nM and 13 nM for EZH2 (WT) and EZH2 (Y641F), respectively.
Pharmacology
EZH2 has been shown to repress the cell cycle inhibitor p21 and other proapoptotic factors, thereby promoting cell cycling in SCLC cells. In various
SCLC cell lines, suppression of EZH2 leads to reduction of cells in S, G2/M phase
with increased p21 expression. EZH2 was also shown to prevent apoptosis by
inhibition of TGF-β via histone methyltransferase methylation of lysine 27in histone H3 (H3K27me3). In addition, it has been shown that in platinum-resistant cancer cells, protein and mRNA expression EZH2 is upregulated and by
silencing EZH2 overcomes drug resistance, making EZH2 a target of interest in SCLC.
in vitro
based on studies from dlbcl cells, it was shown that ei1 suppressed cellular h3k27 methylation and activated expression of ezh2 target gene - p16. ei1 also blocked h3k27 methylation and cell proliferation in mouse embryonic fibroblasts. in addition, ei1 potently and selectively inhibited the growth of dlbcl cells carrying ezh2 mutation, and therefore resulted in cell cycle arrest and apoptosis. [1]
IC 50
a potent and selective suppressor of ezh2 with ic50 values of 15 nm and 13 nm for wild type ezh2 and ezh2 y641f mutant, respectively
References
[1]qia w, chan hm, teng l, li l, chuai s, zhang rp, zeng j, li m, fan h, lin y, gu j, ardayfiob o, zhang jh, yan x, fang j, mi y, zhang m, zhou t, feng g, chen zj, li g, yang t, zhao k, liu x, yu z, lu cx, atadja p and li e. selective inhibition of ezh2 by a small molecule inhibitor blocks tumor cells proliferation. proc natl acad sci. 2012 dec; 109(52): 213605.
