Cancer is a genetic disease, but its development also involves multiple epigenetic alterations. Epigenetics regulates transcription by modulating chromatin architecture through different mechanisms. Hence, dysregulation of such mechanisms can result in aberrant gene expression or silencing, which in turn can lead to carcinogenesis. One of the most relevant epigenetic modifications is the methylation of lysine 27 at histone 3 (H3K27), a broadly known repressive histone mark. H3K27 methylation is incorporated by the polycomb repressive complex 2 (PRC2), a multimeric protein complex formed by four core components: EZH2, EED, SUZ12 and RbAp46/48, all of which are essential for its catalytic activity. Overexpression of PRC2 proteins, particularly of EZH2, results in hyperactivation of the complex and high levels of H3K27m3, which are associated to a myriad of human cancers. Hence, the discovery of PRC2 inhibitors is an area of active research for both the pharmaceutical industry and academic laboratories. The relevance of such compounds is highlighted by the recent accelerated approval of the first in class EZH2 inhibitor (tazemetostat, Epizyme), for the treatment of metastatic or locally advanced epithelioid sarcoma. Here, we describe the design, synthesis and biological evaluation of a new family of stapled peptides as inhibitors of PRC2 metyltransferase activity, designed to target the intramolecular SANT1L-SBD interaction in EZH2. Our lead cyclopeptide showed potent inhibition of H3K27 trimethylation in both in vitro and cellular assays, demonstrating that it is cell permeable and active in physiological conditions. Its inhibition of PRC2 catalytic activity produced a marked dose-dependent antiproliferative effect in metastatic Cakis-1 cells. Notably, in these experiments our compound was almost as effective as GSK126, a well-known orthosteric EZH2 inhibitor. We further present compelling evidences suggesting that our stapled peptide targets selectively PRC2, and more specifically, its catalytic subunit EZH2 in an allosteric fashion. To our knowledge, this bisthioether stapled peptide may well be the first example of such allosteric EZH2 inhibitors described to date. This class of compounds could be extremely valuable in addressing the resistance profiles recently reported in clinical trials with EZH2-SET domain inhibitors, in which extended dosing of these drugs have led to secondary EZH2 mutants resistant to treatment. Our compound’s unique mechanism of PRC2 inhibition, together with its potency, remarkable H3K27me3 inhibition selectivity, and low cytotoxicity to non-cancerous cells demonstrate this stapled peptide’s potential for future development of novel epigenetic cancer therapies.Table 1
Table 1.Structure and Biological Activity of Lead Cyclopeptide.
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