Epigenetic modulation in oncology: in-silico mechanistic studies of emerging enhancer zeste of homolog 2 inhibitors

Enhancer of Zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex 2 (PRC2), plays a central role in epigenetic regulation through histone H3 lysine 27 trimethylation (H3K27me3). Aberrant EZH2 activity is strongly linked to tumorigenesis via silencing of tumor suppressor genes and promotion of oncogenic pathways. In recent years, EZH2 has emerged as a promising therapeutic target, with multiple classes of inhibitors designed to block its methyltransferase function. This review highlights the structural features of EZH2, its interactions with PRC2 components, and its dual roles in both PRC2-dependent and independent oncogenic processes. We summarize recent advances in the design and development of EZH2 inhibitors, including the FDA-approved agent Tazemetostat, next-generation reversible inhibitors (e.g., 15h), and covalent inhibitors (e.g., SKLB-03176), with emphasis on their binding mechanisms and structure–activity relationships. In-silico docking studies further elucidate key interactions within the SAM-binding pocket, offering insights into inhibitor selectivity, resistance mechanisms, and opportunities for optimization. Collectively, these findings underscore the therapeutic potential of EZH2 inhibition in diverse malignancies and provide a framework for the rational design of future epigenetic drugs with improved efficacy and safety profiles.