Therapeutic Horizons in Targeting EZH2 With Dual and Non‐PROTAC Inhibitor Molecules: Recent Achievements, Comparative Analysis, and Future Perspectives

The aberrant overexpression of Enhancer of Zeste Homolog 2 (EZH2) endorses uncontrolled cell proliferation and metastasis across multiple malignancies. These make EZH2 an attractive biological target for the development of potential anticancer molecules. Following the approval of Tazemetostat, the last 5 years have witnessed extensive medicinal chemistry efforts to refine EZH2 inhibitors to explore dual-target hybrids. This review comprehensively surveys the chemical diversity, synthetic approaches, pharmacological activity, and SAR analysis of emerging pyridone- and non-pyridone-based scaffolds that modulate EZH2, either selectively or in combination with other targets, such as PARP, BRD4, HDAC6, or HSP90. A comparative analysis of enzymatic and cytotoxic activities was conducted. Results revealed strong translational correlation for lead compounds, such as N40 and 136, which exhibit sub-nanomolar inhibition and potent cytotoxicity in lymphoma models. Conversely, multitarget hybrids such as Olaparib-Tazemetostat (33) and Tazemetostat-resorcinol (170) maintained robust cellular efficacy through synergistic epigenetic and DNA-repair modulation. The reviewed EZH2 inhibitors illustrate significant progress in improving selectivity and mutation resilience, while highlighting persisting challenges with off-target epigenetic effects and resistance mechanisms. Future perspectives emphasize rational design strategies integrating dual targeting, computational modeling, and covalent functionalities to enhance therapeutic durability. Collectively, these advances explain the evolving therapeutic horizon of non-PROTAC and dual EZH2 inhibitors, offering an outline for next-generation EZH2 inhibitors.