Design, Synthesis, and Evaluation of VHL-Based EZH2 Degraders to Enhance Therapeutic Activity against Lymphoma

Traditional EZH2 inhibitors are developed
to suppress the enzymatic
methylation activity, and they may have therapeutic limitations due
to the nonenzymatic functions of EZH2 in cancer development. Here,
we report proteolysis-target chimera (PROTAC)-based EZH2 degraders
to target the whole EZH2 in lymphoma. Two series of EZH2 degraders
were designed and synthesized to hijack E3 ligase systems containing
either von Hippel–Lindau (VHL) or cereblon (CRBN), and some
VHL-based compounds were able to mediate EZH2 degradation. Two best
degraders, YM181 and YM281, induced robust cell viability inhibition
in diffuse large B-cell lymphoma (DLBCL) and other subtypes of lymphomas,
outperforming a clinically used EZH2 inhibitor EPZ6438 (tazemetostat)
that was only effective against DLBCL. The EZH2 degraders displayed
promising antitumor activities in lymphoma xenografts and patient-derived
primary lymphoma cells. Our study demonstrates that EZH2 degraders
have better therapeutic activity than EZH2 inhibitors, which may provide
a potential anticancer strategy to treat lymphoma.