Polycomb repressive complex 2 (PRC2) is a multicomponent complex with histone methyltransferase (HMT) activity. H3K27 trimethylation (H3K27me3) is a key mechanism responsible for gene repression. In this study, researchers report the discovery of an EED-targeted bivalent chemical degrader. Researchers show that UNC6852 potently binds EED in vitro, degrades EED and other PRC2 components in a highly selective fashion. UNC6852 also inhibits PRC2 catalytic activity resulting, and has antiproliferative effects in DLBCL cell lines.

UNC6852 is an embryonic ectoderm development (EED)-targeted bivalent chemical degrader. Especially, UNC6852 selectively degrades EED, EZH2, and SUZ12 via recruitment of VHL. Moreover, UNC6852 results in loss of PRC2 catalytic activity and decreases H3K27me3 levels. UNC6852 contains an EED226-derived ligand and a ligand for VHL which bind to the WD40 aromatic cage of EED and CRL2VHL, respectively. Degradation of PRC2 with UNC6852 blocks the histone methyltransferase activity of EZH2. UNC6852 degrades both wild-type and mutant EZH2, and additionally displays anti-proliferative effects in this cancer model system.UNC6852 is a bivalent chemical degrader of PRC2 containing an EED ligand (green) and a VHL ligand (coral). Encouragingly, these data suggested that UNC6852 results in a decrease in the levels of both EED and EZH2 at 24 h. In addition, UNC6852 facilitates PRC2 degradation via VHL recruitment.

Overall, UNC6852 selectively degrades PRC2 via the E3 ligase ubiquitylation pathway. UNC6852 results in a decrease in protein levels of both EED and EZH2 over these time points. Importantly, UNC6852 leads to a comparable decrease in H3K27me3 levels, with H3K27me3 reduced by 51% after 72 h. UNC6852 effectively degrades PRC2 components EED, EZH2, and SUZ12 via VHL recruitment and the E3 ligase proteasome degradation pathway.

Frances Potjewyd, et al. Degradation of Polycomb Repressive Complex 2 with an EED-Targeted Bivalent Chemical Degrader. Cell Chem Biol. 2020 Jan 16;27(1):47-56.e15.