EI-1

EI-1 is a potent and selective small molecule inhibitor of the histone methyltransferase EZH2 (Enhancer of Zeste Homolog 2), which serves as the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2). It functions as a S-adenosyl-L-methionine (SAM)-competitive inhibitor, binding to the SET domain of EZH2 to block the tri-methylation of histone H3 at lysine 27 (H3K27me3), an epigenetic modification associated with transcriptional repression. Developed by Novartis, EI-1 has demonstrated significant anti-proliferative activity in preclinical models of B-cell lymphoma, particularly those harboring EZH2 gain-of-function mutations (such as Y641 or A677). By reducing H3K27me3 levels, EI-1 restores the expression of silenced tumor suppressor genes, leading to cell cycle arrest and apoptosis in sensitive cancer cells. While primarily utilized as a chemical probe in research, EI-1 provided critical proof-of-concept for targeting EZH2 in oncology.