Zeste homolog enhancer 2 (EZH2) is one of the core catalytic subunits of PRC2, which mainly mediates histone H3K27 trimethylation to regulate the expression of tumor suppressor genes. Tazemetostat has been approved by the FDA as the first EZH2 inhibitor for the treatment of epithelioid sarcoma in 2020. In recent years, the role of EZH2 in tumor pathophysiology has been further studied, and more and more novel EZH2 inhibitors have been reported and applied in the treatment of lymphoma, prostate cancer, lung cancer and other cancers. In this article, we analyzed and summarized the structural features and the biological activity of various novel EZH2 inhibitors reported since 2018. Simultaneously, we reclassified the reported novel EZH2 inhibitors from the perspective of structure, and discussed their ability to treat malignant tumors and their future development trend. These provides a new strategy for the research of EZH2 inhibitors in medicinal chemistry.

Graphical Abstract