Degradation of Polycomb Repressive Complex 2 with an EED-targeted Bivalent Chemical Degrader

Abstract

Protein degradation via the use of bivalent chemical degraders provides an alternative strategy to block protein function and assess the biological roles of putative drug targets. This approach capitalizes on the advantages of small molecule inhibitors while moving beyond the restrictions of traditional pharmacology. Herein we report a first-in-class chemical degrader (UNC6852) that targets Polycomb Repressive Complex 2 (PRC2). UNC6852 contains an EED226 derived ligand and a ligand for VHL which bind to the WD40 aromatic cage of EED and CRL2 VHL , respectively, to induce proteasomal degradation of PRC2 components, EED, EZH2, and SUZ12. Degradation of PRC2 with UNC6852 blocks the histone methyltransferase activity of EZH2, decreasing H3K27me3 levels in HeLa cells and diffuse large B-cell lymphoma (DLBCL) cells containing an EZH2 Y641N gain-of-function mutation. UNC6852 degrades both wild type EZH2 and EZH2 Y641N , and additionally displays anti-proliferative effects in this cancer model system.

Advances and Opportunities in Epigenetic Chemical Biology

“…The first example of an EZH2 degrader employed the hydrophobic tagging approach, which induces local protein unfolding to enact protein degradation [238] . Subsequently, Potjewyd and co‐workers reported a PROTAC that binds the embryonic ectoderm development (EED) unit in PRC2 and induces proteasomal degradation of EED, EZH2, and SUZ12 in human cells bearing EZH2‐activating mutations [236] . This degradation of multiple PRC subunits was also observed in an independent approach employed by Hsu and co‐workers [235] .…”

PROTACs: great opportunities for academia and industry

“…35). 306 UNC6852 potently degraded EED and EZH2 with DC 50 values of 0.79 ± 0.14 μM and 0.3 ± 0.19 μM, respectively, while SUZ12 showed less degradation. In addition, UNC6852 blocked the histone methyltransferase activity of EZH2 and inhibited the proliferation of DB cells (a DLBCL cell line harboring the EZH2 Y641N mutant) with an EC 50 of 3.4 ± 0.77 μΜ after 9 days of treatment, which was similar to the inhibitors EED226 and UNC1999…”

Therapeutic targeting of chromatin: status and opportunities

“…80% degradation). This compound also degraded EZH2 and had antiproliferative effects [214]. Two other PROTACs were found to degrade EED, EZH2 and SUZ12 in the PRC2 complex [213].…”

“…In 2020, PROTACs targeting the EED subunit of PRC2 were developed [213,214]. These could solve the problem of resistance to EZH1/2 inhibitors (tazemetostat) that had been addressed by using allosteric EED inhibitors.…”