EZH2 PROTACs outperform catalytic inhibitors in prostate cancer by targeting a methylation-independent function of...

Area of Science:

• Epigenetics and Cancer Biology
• Molecular Therapeutics
• Prostate Cancer Research

Background:

• Enhancer of Zeste Homolog 2 (EZH2) is a key driver of prostate cancer (PCa) progression through epigenetic silencing.
• Existing EZH2 catalytic inhibitors (EZH2i) demonstrate limited efficacy in PCa treatment.
• The role of EZH2 in both complex-dependent and independent functions requires further investigation for therapeutic targeting.

Purpose of the Study:

• To design and develop novel VHL-based proteolysis-targeting chimera (PROTAC) degraders of EZH2.
• To evaluate the efficacy of EZH2 PROTACs in degrading EZH2 and its associated proteins in PCa models.
• To elucidate the mechanisms underlying the anti-proliferative effects of EZH2 PROTACs and compare them to existing EZH2 inhibitors.

Main Methods:

• Design and synthesis of VHL-based PROTACs utilizing EPZ-6438 as an EZH2 ligand.
• Assessment of EZH2 and Polycomb Repressive Complex 2 (PRC2) subunit degradation in various PCa cell lines.
• Analysis of androgen receptor (AR) and coactivator (e.g., p300) levels, and evaluation of anti-proliferative activity, p21 expression, and cellular senescence.

Main Results:

• A lead compound, PROTAC-6272, effectively degraded EZH2 and other PRC2 subunits in PCa cells.
• EZH2 PROTACs failed to decrease androgen receptor (AR) and did not degrade EZH2 coactivators like p300, indicating an inability to engage EZH2 outside the PRC2 complex.
• PROTAC-6272 demonstrated superior anti-proliferative activity compared to EPZ-6438 in some PCa models, inducing p21 expression and cellular senescence via a methylation-independent PRC2 function.

Conclusions:

• EZH2i-based PROTACs, while not targeting all PRC2-independent functions of EZH2, offer therapeutic advantages over traditional EZH2 inhibitors.
• PROTAC-6272 effectively degrades EZH2 within the PRC2 complex and disrupts a methylation-independent function, leading to anti-cancer effects.
• These findings suggest that targeting methylation-independent functions of EZH2 through PROTACs holds therapeutic potential for specific prostate cancer contexts.