PROTAC Linkerology Leads to an Optimized Bivalent Chemical Degrader of Polycomb Repressive Complex 2 (PRC2) Components

Bivalent chemical degraders, otherwise known as proteolysis-targeting
chimeras (PROTACs), have proven to be an efficient strategy for targeting
overexpressed or mutated proteins in cancer. PROTACs provide an alternative
approach to small-molecule inhibitors, which are restricted by occupancy-driven
pharmacology, often resulting in acquired inhibitor resistance via
compensatory increases in protein expression. Despite the advantages
of bivalent chemical degraders, they often have suboptimal physicochemical
properties and optimization for efficient degradation remains highly
unpredictable. Herein, we report the development of a potent EED-targeted
PRC2 degrader, UNC7700. UNC7700 contains a unique cis-cyclobutane linker and potently degrades PRC2 components EED (DC50 = 111 nM; Dmax = 84%), EZH2WT/EZH2Y641N (DC50 = 275 nM; Dmax = 86%), and to a lesser extent SUZ12 (Dmax = 44%) after 24 h in a diffuse large B-cell
lymphoma DB cell line. Characterization of UNC7700 and related compounds
for ternary complex formation and cellular permeability to provide
a rationale for the observed improvement in degradation efficiency
remained challenging. Importantly, UNC7700 dramatically reduces H3K27me3
levels and is anti-proliferative in DB cells (EC50 = 0.79
± 0.53 μM).