Therapeutic horizons in the development of PROTAC-based EZH2 inhibitors: recent achievements, comparative analysis,...

EZH2, a histone methyltransferase and the catalytic subunit of the polycomb repressive complex 2 (PRC2), plays a pivotal role in tumor epigenetics through transcriptional repression of tumor suppressor genes. Despite the clinical success of tazemetostat, classical small-molecule inhibitors face limitations related to incomplete target occupancy, adaptive resistance, and non-catalytic EZH2 functions. These challenges have driven a paradigm shift toward proteolysis-targeting chimeras (PROTACs)-bifunctional molecules that inhibit EZH2 through E3 ligase-mediated ubiquitination and proteasomal degradation. This review discusses the design principles, synthetic approaches, structural diversity, and pharmacological profiles of recently developed VHL-, CRBN-, and cIAP-recruiting EZH2 inhibitors reported in the last five years. Comparative analysis of enzymatic inhibition, cellular cytotoxicity, and degradation kinetics highlights MS8847 (84) as a verified degrader (DC₅₀ = 34 nM in EOL-1 cells) with concentration- and time-dependent activity, establishing a benchmark for efficient EZH2 elimination. Compounds P3 (72) and P4 (73) (VHL-based) and U3i (44) (CRBN-based) also demonstrated potent dual biochemical and cellular profiles. Recent findings emphasize structure-activity trends, ligase selectivity, and linker optimization as decisive parameters for balancing efficacy and selectivity. Future directions focus on integrating novel ligases, proteome-wide selectivity mapping, and computational modeling to refine degradation efficiency and minimize off-target effects. Collectively, these developments explain a transformative therapeutic horizon where EZH2-targeting PROTACs are dignified to overcome the intrinsic limitations of enzyme inhibition, offering a new era of epigenetic cancer therapy through targeted protein degradation.