The traditional view is that cancer originates from the accumulation of somatic mutations, but many studies in recent years have found that epigenetic abnormalities are an important factor leading to tumorigenesis. At present, epigenetic changes can be used as biomarkers for cancer and can even be targeted by cancer treatment. As an important role in the epigenetic modification process, EZH2 has multiple targeted drugs approved for marketing and entered the late clinical stage, and has become a highly concerned anti-tumor target.

Close connection between EZH2 gene and cancer

The Zeste enhancer homolog 2 (EZH2) gene is one of the important members of the PcG family of epigenetic regulatory factors, and is also the catalytic subunit of Polycomb Repressive Complex 2 (PRC2). It plays a vital role in the H3 methylation pathway and plays an important role in the epigenetic modification process.

Studies have found that EZH2 expression is elevated in a variety of tumors. It inhibits the transcription of target genes by directly methylating a variety of target molecules, directly binding to specific molecules, or binding to the promoter region of target genes and affecting gene transcription, and participates in the occurrence, development, metastasis, drug resistance and immune regulation of tumors. Studies have found that melanoma, breast cancer, prostate cancer, lung cancer and liver cancer, psoriasis, hematological malignancies and other diseases are all associated with EZH2 mutations and expression imbalances, so EZH2 inhibitors are expected to play an important role in anti-tumor therapy.

Carcinogenic mechanism of EZH2

The most important biological function of EZH2 is the regulation of transcription, which regulates its downstream genes and proteins through PRC2-dependent or PRC2-independent methylation, or in a PRC2- and methylation-independent manner. EZH2 dysregulation accelerates cell proliferation and prolongs cell survival, leading to the occurrence and development of cancer. Several studies have found that EZH2 is overexpressed in a variety of solid tumors, including breast cancer, lung cancer, colorectal cancer, prostate cancer, and gastric cancer. High levels of EZH2 are associated with poor prognosis and tumor invasiveness in these cancers. In hematological tumors, EZH2 can affect the proliferation, invasion, and metastasis of hematological tumors by inhibiting the expression and transcription of tumor suppressor genes.

Role of EZH2 in cancer cell metastasis

Several experiments have demonstrated the potential role of EZH2 in cancer cell metastasis. In an in vivo experiment, melanoma-positive lymph nodes and distant lung metastases continued to develop in control melanoma model mice; while in EZH2 knockout mice, lymph node metastasis was significantly reduced and lung metastasis was almost non-existent, demonstrating the important role of EZH2 in cancer cell metastasis. Other studies have shown that EZH2 can promote epithelial-mesenchymal transition and tumor angiogenesis in cancer cells.

Role of EZH2 in tumor cell immune escape and drug resistance

Studies have found that EZH2 inhibits the expression of DNA methyltransferase 3A (DNMT3A) in cervical cancer, causing immune tolerance and immune escape in the process of carcinogenesis; in glioblastoma (GBM), the EZH2-92aa protein encoded by cyclic EZH2 can induce GBM stem cells (GSCs) to escape immune responses to NK cells by inhibiting the binding of NKG2D to cell surface ligands.

EZH2 is associated with targeted drug resistance. EZH2 induces acquired resistance to gefitinib in non-small cell lung cancer (NSCLC) by activating the phosphoinositide 3-kinase (PI3K)/AKT pathway. Studies have also found that EZH2 is negatively correlated with resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). EZH2 also regulates cisplatin resistance in ovarian cancer through the avian myelocytic tumor virus oncogene cell homolog (c-Myc)-miR-137-EZH2 axis.

Types of EZH2 inhibitors

Currently, EZH2 inhibitors are mainly divided into two categories: inhibitors that inhibit EZH2 methyltransferase activity and inhibitors that destroy PRC2 structure. The former can be further divided into EZH2 inhibitors that indirectly inhibit EZH2 by inhibiting SAH hydrolase, and EZH2 inhibitors that compete with SAM for binding to the SET active site.

Inhibitors that inhibit EZH2 methyltransferase activity

There are two main categories of inhibitors that inhibit EZH2 methyltransferase activity: S-adenosylhomocysteine (SAH) hydrolase inhibitors and S-adenosylmethionine (SAM) competitive inhibitors. SAH hydrolase inhibitors are not specific inhibitors of EZH2, lack selectivity, have greater toxicity, and hinder research and development progress.

EZH2 inhibitors that compete with SAM for binding to the SET active site are more specific, and are divided into two types: those targeting EZH2 and EZH1/2. EZH1 is a highly related homologous gene of EZH2. EZH1 and EZH2 show complementary functions in tumor cells, especially when EZH2 function is lost, EZH1 can maintain the level of H3K27me3 and promote the survival and proliferation of tumor cells. Currently available tazetostat and valmetuzin, as well as most EZH2 inhibitors entering clinical research, are SAM competitive inhibitors, among which valmetuzin is a dual inhibitor of EZH1/EZH2.

Inhibitors that disrupt PRC2 structure

Inhibitors that disrupt PRC2 structure weaken its function by interfering with the multimeric integrity of the PRC2 complex, such as EZH2-EED protein interaction and EED inhibitors as indirect regulators of PRC2-dependent methyltransferase activity. Johnson & Johnson's H1 histamine receptor antagonist Astemizole is reported to inhibit the proliferation of PRC2-driven lymphoma cells by destroying the EZH2-EED complex. AXT-1003, developed by Novartis and Estocon, triggers and promotes protease-mediated EZH2 degradation by allosteric binding to EZH2. It is reported that it has shown superior anti-tumor activity and better safety than similar drugs in preclinical studies and has entered clinical phase I studies. Other EZH2 inhibitors of this type are mostly in the preclinical research stage.

R&D progress of EZH2 inhibitors

Analysis of EZH2 inhibitors on the market

Currently, there are 2 EZH2 inhibitors on the market worldwide. IPSEN's EZH2 inhibitor tazemetostat was approved for marketing in the United States in 2020 (trade name: Tazverik®) for the treatment of adult patients with metastatic or locally advanced epithelioid sarcoma (ES) who are not suitable for complete resection and pediatric patients aged 16 years and above and adult patients with relapsed or refractory (R/R) follicular lymphoma (FL). The results of a Phase II clinical study of tazemetostat showed that the overall response rate (ORR) of monotherapy for patients with EZH2 mutant and EZH2 wild-type relapsed/refractory follicular lymphoma was 69% and 35%, respectively, and the median progression-free survival (PFS) was 13.8 months and 11.1 months, respectively. Tazemetostat will have global sales of more than $40 million in 2023 and is being developed for multiple types of hematological tumors and genetically defined solid tumors (synovial sarcoma, castration-resistant prostate cancer, etc.).

Daiichi Sankyo's EZH1/2 dual inhibitor valmetuxostat was approved for marketing in Japan in 2022 (trade name: Ezharmia®) for the treatment of adult patients with relapsed or refractory T-cell leukemia/lymphoma (ALT). The results of a Phase II clinical study of valmetuxostat showed that it showed an objective response rate of 48% in previously treated relapsed or refractory T-cell leukemia/lymphoma (ATL), with complete responses observed in 20% of patients and partial responses observed in 28% of patients. For Japanese patients with aggressive ATL subtypes, the median overall survival was as long as 12 months.

In addition, some data also include the H1 histamine receptor antagonist astemizole in the approved EZH2 inhibitors, because it can inhibit the proliferation of PRC2-driven lymphoma cells by destroying the EZH2-EED complex, and can also play the relevant role of EZH2 inhibitors.

Analysis of the pipeline of EZH2 inhibitors under development

No EZH2 inhibitors have been approved for marketing in China. In 2021, Hutchison Medicine obtained the rights to research, develop, produce and commercialize tadalafil in Greater China. In 2022, tadalafil was approved for clinical urgent import drug application and used in Hainan Pilot Zone. Currently, tadalafil has applied for listing in China in 2023 and has been included in the priority review by CDE.

Among the domestic EZH2 inhibitor pipeline under development, SHR2554 is a new oral EZH2 inhibitor independently developed by Hengrui Medicine. It has been applied for listing and accepted by CDE in October 2024, and is included in the priority review and approval process. It is intended to be used for the treatment of relapsed or refractory peripheral T-cell lymphoma that has received at least 1 line of systemic treatment. In February 2023, Hengrui Medicine granted the development, production and commercialization rights of SHR-2554 to Treeline Biosciences in the United States outside of Greater China, and the total transaction amount may exceed US$700 million. Sinovent's XNW5004 received CDE breakthrough therapy designation in September 2024 and is also used to treat relapsed or refractory peripheral T-cell lymphoma. The domestic EZH2 inhibitor pipeline with rapid progress also includes Haihe Pharmaceutical's EZH1/2 dual inhibitor HH2853.
Future prospects of EZH2 inhibitors

Progress of EZH2 inhibitors in solid tumors

The indications of EZH2 inhibitors currently on the market and in clinical research are mainly concentrated in blood tumors. Studies have shown that EZH2 inhibitors have limited therapeutic effects on most solid tumors. The main reason is that EZH2 inhibitors reduce H3K27me3 while increasing histone 3 lysine 27 acetylation (H3K27ac), which leads to EZH2 inhibitor resistance. Several studies have reported that Bromodomain-containing protein 4 (BRD4) inhibitors can enhance the sensitivity of solid tumors to EZH2 inhibitors. EZH2-BRD4 dual inhibitors have shown effective antiproliferative activity against breast cancer, lung cancer, bladder cancer, and pancreatic cancer cells in experiments, showing the potential of EZH2-BRD4 dual inhibitors as a breakthrough in the treatment of solid tumors with EZH2 inhibitors.

EZH2-PROTAC

PROTAC has become one of the focuses of tumor treatment research. Currently, a number of degraders based on EZH2 small molecule enzyme inhibitors have been developed. Some EZH2-PROTACs have shown efficacy beyond traditional EZH2 enzyme inhibitors in research. For example, in a study in 2022, researchers used PROTAC to develop a degrader MS177, targeting the characteristics of EZH2's classical (EZH2-PRC2) and non-classical (EZH2-TAD-cMyc-coactivators) activities that promote tumorigenesis. The degrader effectively inhibited the proliferation of multiple myeloma (MM) cells in vitro and in vivo, and showed strong proliferation inhibition activity in a series of human prostate cancer cell lines. Other EZH2-PROTACs that have been discovered, such as MS1943 and MS8815, also showed efficacy against triple-negative breast cancer and showed good prospects in preclinical studies.

EZH2 inhibitors that affect protein expression by regulating PPI through small molecules

In the study of the dynamic process of PRC2 complex dissociation, researchers found that not only the loss of any single key component protein of the complex will cause the degradation of other component proteins of PRC2, but also if the complex protein interaction (PPI) is disturbed or destroyed, it will also cause the level of each component protein to be downregulated. This makes disrupting the EZH2 embryonic ectoderm development (EED) protein-protein interaction (PPI) a new potential cancer treatment strategy. For example, in a 2021 study, researchers optimized the stronger-affinity DC-PRC2in-01 based on the antihistamine astemizole, a PPI inhibitor of EZH2-EED; the new compound LG1980 can disrupt the interaction between EED and EZH2, thereby inducing protein degradation of EZH2 and inhibiting the phosphorylation and activity of EZH2, which is expected to overcome the chemotherapy resistance of prostate cancer.

EZH2 promotes tumorigenesis, metastasis and immune escape by regulating histone methylation, and is closely related to a variety of solid tumors and hematological tumors. At present, EZH2 inhibitors can be divided into two categories: drugs that inhibit methyltransferase activity and drugs that destroy the structure of the PRC2 complex. Among the former, SAM competitive inhibitors account for the majority of currently marketed and under-development drugs. There are two EZH2 inhibitors on the market worldwide. Hengrui Medicine's SHR2554 and Sinovent's XNW5004 have made significant progress in China and have entered priority review or late clinical trials. Future directions include overcoming solid tumor resistance (such as EZH2-BRD4 dual inhibitors), developing PROTAC degraders, and new strategies to interfere with EZH2-EED protein interactions. These advances highlight the broad potential of EZH2 inhibitors in tumor treatment. With the launch of more new EZH2 inhibitors and their expansion into the field of solid tumor treatment, more treatment options will be available to patients in the future.

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