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

Abstract

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.