Therapeutic horizons in the development of PROTAC-based EZH2 inhibitors: recent achievements, comparative analysis, and future perspectives
Abstract
= 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.
Fields of Study & Subjects
Protein Degradation and Inhibitors
Epigenetics and DNA Methylation
Histone Deacetylase Inhibitors Research
Publication details
- Journal / source
- RSC Advances
- Publisher
- Royal Society of Chemistry (RSC)
- Volume
- 16
- Issue
- 4
- Pages
- 3034–3056
- Publication date
- 1 January 2026
- Language
- EN