Structure of the PRC2 complex and application to drug discovery

Abstract

The polycomb repressive complexes 2 (PRC2) complex catalyzes tri-methylation of histone H3 lysine 27 (H3K27), a repressive chromatin marker associated with gene silencing. Overexpression and mutations of PRC2 are found in a wide variety of cancers, making the catalytic activity of PRC2 an important target of cancer therapy. This review highlights recent structural breakthroughs of the human PRC2 complex bound to the H3K27 peptide and a small molecule inhibitor, which provide critically needed insight into PRC2-targeted drug discovery.

Telomere dysfunction cooperates with epigenetic alterations to impair murine embryonic stem cell fate commitment

“…UNC2400 and A395N are structurally related to UNC1999 and A395 respectively, but exhibit a reduced inhibition activity against PRC2 (He et al, 2017;Konze et al, 2013) (for further details refer to Materials and Methods). These inhibitors were chosen because of the extensive biochemical and in vivo data to establish their specificity for their cognate substrates (He et al, 2017;Konze et al, 2013;Shi et al, 2017). Although Ezh2 mRNA was slightly lower in undifferentiated Tert -/-ESCs compared with WT ESCs, Ezh2, Suz12, and Eed continued to be expressed after differentiation at levels that did not significantly differ from WT ESCs (Figure 2-figure supplement 1B).…”

MiR-34 inhibits polycomb repressive complex 2 to modulate chaperone expression and promote healthy brain aging

“…Our discovery of the PRC2 complex as a key modulator of a healthy brain transcriptome in Drosophila may extend to the vertebrate brain, as miR-34 seed sequences are present in the 3′UTRs of vertebrate homolog of Pcl , PHF19 . Small molecules that target epigenetic modulation of the genome are in development as cancer therapeutics 49 , 50 . These findings thus raise the possibility that mitigating PRC2 activity, through gene or small molecule approaches, may lead to healthier brain aging and protection from associated deleterious consequences, such as cognitive decline and neurodegenerative disease.…”

Thiadiazole derivatives as anticancer agents

“…EZH2 is a member of the polycomb repressive complexes 2 (PRC2) that catalyzes the methylation of histone H3 lysine 27 (H3K27), which in turn mediates chromatin compaction. Overexpression of EZH2 is observed in numerous cancer of different origin and its inactivation was therapeutically effective in several cancer models [17]. Of note, the other components of PRC2 and the global H3K27 methylation, modified by EZH2, remained unaffected by NSC745885 treatment.…”