Abstract
Dysregulation of the histone methyltransferase Polycomb repressive complex 2 (PRC2) results in aberrant silencing of tumor suppressors and activation of oncogenes. Targeting PRC2 with compounds holds significant potential for both basic research and therapeutic applications. Here, we leveraged extensive structural studies of PRC2 to design a cyclic peptide that robustly activates PRC2. Structure-activity relationship studies guided the functional optimization of this cyclic peptide, yielding a Phenylalanine-type (Phe-type) cyclic peptide with approximately eight-fold activation compared to that of the poised state of PRC2. A 3.3Å cryo-electron microscopy structure of the PRC2-peptide complex, combined with biochemical analyses, revealed a shift in the H3K27 methylation from mono- (me1) and dimethylation (me2) to trimethylation (me3). Finally, we demonstrated that the cyclic peptide exhibits improved mouse plasma stability and can also be readily taken up by cells which results in a shift of the H3K27 methylation landscape to trimethylation, similar to the observed effects in vitro. These findings support the utility of such molecules for probing PRC2 activation and targeting dysregulated H3K27 methylation in cancer.