Ezh2 (Enhancer of zeste homolog 2) protein is the enzymatic component of the 
Polycomb repressive complex 2 (PRC2), which represses gene expression by 
methylating lysine 27 of histone H3 (H3K27) and regulates cell proliferation and 
differentiation during embryonic development. Recently, hot-spot mutations of 
Ezh2 were identified in diffused large B-cell lymphomas and follicular 
lymphomas. To investigate if tumor growth is dependent on the enzymatic activity 
of Ezh2, we developed a potent and selective small molecule inhibitor, EI1, 
which inhibits the enzymatic activity of Ezh2 through direct binding to the 
enzyme and competing with the methyl group donor S-Adenosyl methionine. 
EI1-treated cells exhibit genome-wide loss of H3K27 methylation and activation 
of PRC2 target genes. Furthermore, inhibition of Ezh2 by EI1 in diffused large 
B-cell lymphomas cells carrying the Y641 mutations results in decreased 
proliferation, cell cycle arrest, and apoptosis. These results provide strong 
validation of Ezh2 as a potential therapeutic target for the treatment of 
cancer.