An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED

Abstract

Polycomb repressive complex 2 (PRC2) consists of three core subunits, EZH2, EED and SUZ12, and plays pivotal roles in transcriptional regulation. The catalytic subunit EZH2 methylates histone H3 lysine 27 (H3K27), and its activity is further enhanced by the binding of EED to trimethylated H3K27 (H3K27me3). Small-molecule inhibitors that compete with the cofactor S-adenosylmethionine (SAM) have been reported. Here we report the discovery of EED226, a potent and selective PRC2 inhibitor that directly binds to the H3K27me3 binding pocket of EED. EED226 induces a conformational change upon binding EED, leading to loss of PRC2 activity. EED226 shows similar activity to SAM-competitive inhibitors in blocking H3K27 methylation of PRC2 target genes and inducing regression of human lymphoma xenograft tumors. Interestingly, EED226 also effectively inhibits PRC2 containing a mutant EZH2 protein resistant to SAM-competitive inhibitors. Together, we show that EED226 inhibits PRC2 activity via an allosteric mechanism and offers an opportunity for treatment of PRC2-dependent cancers.

Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens

“…These results are consistent with previous observations in cancer cell lines that depletion of SUZ12, a subunit of the EZH2/1-PRC2 complex, resulted in the expression of a class of ISGs whose promoters exhibited bivalent (H3K27me3 and H3K4me3) histone methylation markers (54). The results are also complemented by analyses of data sets (GEO data set GSE81267) published by Qi et al (28) where treatment of Karpas422 cancer cells with a novel inhibitor targeting the PRC2 subunit EED (EED226) induced antipathogen gene cascades that parallel the inflammatory and stress pathways shown here ( Fig. S2C and D; Table S1C).…”

“…Recently, inhibitors of the histone H3K27 methyltransferases EZH2/1 have been developed on the basis of the potential to treat some diffuse large B-cell, follicular, and non-Hodgkin's lymphomas (23,(55)(56)(57). Importantly, pharmacological inhibition of EZH2/1 has shown promising results in tumor regression in cancer cell lines, mouse tumor xenograft models, and human phase I trials (7,23,(25)(26)(27)(28)(29)(30)58).…”

“…More recently, inhibitors of the histone H3K27 methyltransferases EZH2 and EZH1 (EZH2/1) have been developed as potential therapeutics for treating cancers with EZH2 gain-of-function mutations (22)(23)(24)(25)(26)(27)(28)(29)(30). As components of Polycomb repressive complex 2 (PRC2), EZH2/1 mediate gene repression primarily through propagation of H3K27me3, which results in domains of nucleosomal compaction (31)(32)(33).…”

WD40 repeat domain proteins: a novel target class?

“…At the top of the list, at least 49 WDR proteins are known to participate in the regulation of gene expression. Among these, 15 are components of chromatin complexes, including EED and WDR5, for which potent inhibitors have been reported 24–26 . WDRs are also found in pathways that are targeted by existing drugs, such as DNA repair or the immune system, in emerging areas of drug discovery, such as chromatin mediated signaling or splicing, and in cellular networks that have so far proven largely undruggable, such as the extensive ubiquitin-proteasome system (UPS) that exerts post-translational control over most of the proteome.…”

Epigenetic regulatory mutations and epigenetic therapy for multiple myeloma

“…Since the interaction of EED with EZH2 is essential for activity of the PRC2 complex (82–85), a small molecule was developed to target the alpha-helical domain of EZH2 that binds EED, which disrupts PRC2 complex interaction (79). A recent inhibitor against the H3K27me3 binding pocket of EED has been developed (86). …”