厦门大学学报（自然科学版）2026，Vol.65Issue(1)：16-28,13.DOI:10.6043/j.issn.0438-0479.202504008
表观遗传甲基化酶EZH2双功能小分子抑制剂的研究进展
Research progress on bifunctional small molecule inhibitors of the epigenetic methyltransferase EZH2
摘要
Abstract
[Background]Cancer is one of the major lethal diseases that threaten human health worldwide.The high incidence rate,mortality,and economic burden are among the top issues concerning cancer patients and their families.To address this challenge,researchers have conducted intensive studies to discover innovative anticancer drugs and develop new therapeutic strategies.Polycomb inhibitory complex 2(PRC2)as an important epigenetic regulatory complex has been found to play a crucial role in cell differentiation,development,and identity maintenance.PRC2 consists of four core proteins,including enhancer of Zeste homolog 2(EZH2),embryonic ectoderm development(EED),suppressor of Zeste 12(SUZ12)and retinoblastoma associated protein 46/48(RbAp46/48).Among them,EZH2(catalytic subunit)serves as an epigenetic methyltransferase that catalyzes the trimethylation of histone H3 lysine 27(H3K27me3),leading to gene repression.Abnormal expression or functional mutation of EZH 2 are closely related to the occurrence of lymphoma,breast cancer,prostate cancer and other cancers.Inhibiting the methyltransferase activity of EZH2 and restoring the expression of tumor suppressor genes have become an important strategy for inhibiting tumor growth.EZH2 is overexpressed or undergoes acquired mutations in many malignant tumors.The first EZH2 inhibitor Tazemetostat(EPZ-6438)was approved by the US Food and Drug Administration(FDA)for the treatment of epithelioid sarcoma and follicular lymphoma,marking an important breakthrough in the clinical application of EZH2 inhibitors.However,current EZH2 inhibitors face limitations,including modest cytotoxicity and narrow therapeutic efficacy in hematological cancers with solid tumors often exhibiting drug resistance.The development of novel EZH2 bifunctional inhibitors that simultaneously target EZH2 and another key target protein may overcome the above problems.[Progress]Research on EZH2 bifunctional small molecule inhibitors has demonstrated a wide range of anti-tumor effects,and has significantly enhanced anti-tumor efficacy by synergistically targeting EZH2 and another target protein(BRD4,G9a,HSP90,HDAC,LSD1,PARP and HIF-1).These newly developed bifunctional inhibitors have shown significantly improved anti-tumor activity in diverse cancers that are insensitive or resistant to single-target inhibitors.In addition,proteolysis targeting chimera(PROTAC),as an emerging targeted protein degradation strategy,selectively degrades target proteins by utilizing the cellular natural ubiquitin proteasome system.EZH2 PROTACs simultaneously inhibit target protein EZH2 and bind to E3 ubiquitin ligases,and thus can be considered as a special type of bifunctional EZH2 inhibitors.PROTACs have achieved improved therapeutic effects than the corresponding conventional inhibitors.Compared with commonly used drug combinations,bifunctional drugs have advantages such as avoiding adverse drug-drug interactions,optimizing pharmacokinetic properties,and reducing acute or delayed toxicity.This review summarizes the research progress in EZH2-targeting bifunctional small molecule inhibitors including EZH 2 PROTACs over the past five years.[Perspective]Although research on EZH2 bifunctional inhibitors has made significant progress,it still faces challenges such as target selectivity,bioavailability pharmacokinetics,and drug resistance.Future research may focus on the following areas.First,bifunctional small molecule inhibitors of EZH2 can be further improved through structural optimization to enhance the target selectivity and bioavailability,pharmacokinetic properties of dual functional inhibitors,while to reduce toxicity.Second,in addition to existing protein targets,bifunctional inhibitors of EZH2 with other epigenetic regulatory factors or signaling pathway proteins can be explored to expand drug types and enhance synergistic effects.Third,it is necessary to systematically study the drug resistance mechanisms of bifunctional inhibitors and develop corresponding strategies to overcome them,such as combination therapy or the development of multi-target PROTAC molecules,in order to address the heterogeneity and adaptability of tumors.Finally,strengthening preclinical and clinical research on bifunctional inhibitors,evaluating their efficacy and safety in different types of cancer,and promoting their transition from laboratory to clinical application are essential.Overall,through interdisciplinary collaboration and continuous innovation,EZH2 bifunctional inhibitors are expected to achieve greater breakthroughs in cancer therapy,providing new hope for improving patient prognosis.关键词
表观遗传/Zeste增强子同源物2(EZH2)/双功能小分子抑制剂/抗肿瘤/耐药Key words
epigenetic/enhancer of Zeste homolog 2(EZH2)/bifunctional small molecule inhibitor/anticancer/drug resistance分类
医药卫生引用本文复制引用
朱大潜,喻振韩,文石军..表观遗传甲基化酶EZH2双功能小分子抑制剂的研究进展[J].厦门大学学报（自然科学版）,2026,65(1):16-28,13.基金项目
广东省科技计划项目(2022A0505050034) （2022A0505050034）
