Targeting Triple-Negative Breast Cancer by a Novel Proteolysis Targeting Chimera Degrader of Enhancer of Zeste Homolog 2

Enhancer of zeste homolog 2 (EZH2),
a catalytic subunit of polycomb
repressive complex 2 (PRC2), is overexpressed in triple-negative breast
cancer (TNBC), correlating with poor prognosis. However, EZH2 catalytic
inhibitors are ineffective in suppressing the growth of TNBC cells
that are dependent on EZH2. Knockdown of EZH2 inhibits the proliferation
of these cells, suggesting that EZH2 protein overexpression but not
its catalytic activity is critical for driving TNBC progression. Several
proteolysis targeting chimera (PROTAC) degraders of EZH2, including
the von Hippel–Lindau (VHL)-recruiting PROTAC YM281, have been
reported. However, the effects of these EZH2 PROTACs in TNBC cells
were not investigated. Here, we report the discovery and characterization
of a novel, potent, and selective EZH2 PROTAC degrader, MS8815 (compound 16), which induced robust EZH2 degradation in a concentration-,
time-, and proteasome-dependent manner in TNBC cells. Importantly, 16 effectively suppressed the cell growth in multiple TNBC
cell lines and primary patient TNBC cells.