The enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and a catalytic subunit of polycomb repressive complex 2 (PRC2) catalyzes trimethylation of lysine 27 of histone 3 (H3K27me3) and further alters downstream target gene levels. The genesis, progression, metastasis and invasion of many cancers have been strongly correlated with hyperactivity of EZH2 through modulating critical gene expression. Recent studies have shown that depending on whether H3K27me3 is present or not and the various biological settings, EZH2 can also operate as a transcriptional co-activator. Here we report the use of computational tools in the development of a staple peptide that selectively binds and disrupts an intermolecular interaction within EZH2, which is crucial for PRC2 proper assembly and function. Cellular treatment with these compounds has shown a dose dependent inhibition of H3K27me3 and growth arrest through disruption of PRC2 assembly. Further, Molecular dynamic simulation, pull down and direct binding assays have validated the binding of these compounds specifically to EZH2. These compounds will help address the challenge of resistance faced by orthosteric inhibitors and provide grounds for the studies of the downstream effectors of the non-conical EZH2 function through its unique mechanism of action (MOA).
