Among the identified candidate genes, MYC repression was found in all patient samples and tested experimental conditions, possibly underscoring the impact of the myc protooncogene in this particular therapeutic setting. Histones are small proteins critical to the efficient packaging of DNA in the nucleus. DNA winds itself around the surface of the histones, forming DNA-protein complexes known as nucleosomes. The N-terminal histone tail protrudes from the nucleosome, allowing for post-translational modification of key histone residues. These post-translational modifications commonly consist of phosphorylation, acetylation, methylation, ubiquitylation, ribosylation, and sumoylation, to name a few. Combinations of such histone modifications take part in the regulation of DNA transcription and constitute an additional level to the genetic code, termed the “histone code”. These modifications are dynamically maintained by various histone-modifying enzymes that control their transfer and removal. While histone-modifying enzymes are important for normal cell function, overexpression of the enzymes can result in the aberrant silencing of genes that are required to govern cell identity. For example, enhancer of zeste homolog 2 is a SET-domain containing histone methyltransferase that catalyzes the diand trimethylation of the lysine at position 27 of histone H3. Both methylation states of H3K27 have been linked to heterochromatic genomic regions and to epigenetic silencing. Overabundance of EZH2 has been linked to the silencing of more than 100 genes in prostate 
cell lines, including several important tumor suppressors. For this reason, the overexpression of EZH2 has been correlated to the invasiveness of breast and prostate cancer and linked to various other cancer types. Moreover, recurrent mutations of EZH2 have been found in germinal center B-cell like diffuse large B-cell lymphoma, follicular lymphoma, and melanoma. The mutated residues alter the substrate specificity of EZH2 and facilitate the conversion from a dimethylated to a trimethylated state, thus resulting in significantly elevated global H3K27me3 levels. Cancer cells harboring EZH2 mutations were recently shown to be dependent on the EZH2 catalytic activity since their viability was severely affected by EZH2 small molecule inhibitors. Additionally, studies have shown that RNAi mediated knockdown of EZH2 inhibits the growth and migration of cancer cells and upregulates the tumor suppressor gene BRCA1. This makes the inhibition of histone-modifying enzymes, in particular EZH2, an important target in the development of cancer therapeutics for many different cancer types. Histone methyltransferase small molecule inhibitors obtained through random, large-scale screening of compound libraries have been reported in the literature. However, the number of potent and selective inhibitors remains small and the community still does not have Doxorubicin adequate tools to target all methyltransferases that are implicated in human disease. For this reason EZH2 remains an important target for inhibitor design. The pharmacological properties of peptidic inhibitors make their use in the development of cancer therapeutics TWS119 difficult. However, the specificity with which they can act with their binding partner make them desirable for the development of chemical probes for the interrogation of methyltransferase and chromatin biology. Peptide inhibitors are generally more specific than small molecule inhibitors as they often more closely resemble the natural binders of many target proteins. The aim of this work was to find specific peptidic inhibitors of EZH2 using a computational de novo peptide design framework.