Covalent inhibitors of EZH2: Design, synthesis and evaluation

Zhang, Qiangsheng; Chen, Xinyi; Hu, Xi; Duan, Xianjie; Wan, Guoquan; Li, Lü; Feng, Qiang; Zhang, Yiqian; Wang, Ningyu; Yu, Luoting

doi:10.1016/j.biopha.2022.112617

Cited by 8 publications

(5 citation statements)

References 32 publications

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“…There are some limitations associated with EZH2 inhibitors that should be considered for their clinical application. The poor efficacy, large molecular weight and poor bioavailability are most important drawbacks of EZH2 inhibitors [ 87 ]. For instance, TAZVERIK™ is a commercial EZH2 inhibitor that should be used with dose of 800 mg twice daily.…”

Section: Ezh2 Inhibitors: An Overviewmentioning

confidence: 99%

The long and short non-coding RNAs modulating EZH2 signaling in cancer

et al. 2022

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Non-coding RNAs (ncRNAs) are a large family of RNA molecules with no capability in encoding proteins. However, they participate in developmental and biological processes and their abnormal expression affects cancer progression. These RNA molecules can function as upstream mediators of different signaling pathways and enhancer of zeste homolog 2 (EZH2) is among them. Briefly, EZH2 belongs to PRCs family and can exert functional roles in cells due to its methyltransferase activity. EZH2 affects gene expression via inducing H3K27me3. In the present review, our aim is to provide a mechanistic discussion of ncRNAs role in regulating EZH2 expression in different cancers. MiRNAs can dually induce/inhibit EZH2 in cancer cells to affect downstream targets such as Wnt, STAT3 and EMT. Furthermore, miRNAs can regulate therapy response of cancer cells via affecting EZH2 signaling. It is noteworthy that EZH2 can reduce miRNA expression by binding to promoter and exerting its methyltransferase activity. Small-interfering RNA (siRNA) and short-hairpin RNA (shRNA) are synthetic, short ncRNAs capable of reducing EZH2 expression and suppressing cancer progression. LncRNAs mainly regulate EZH2 expression via targeting miRNAs. Furthermore, lncRNAs induce EZH2 by modulating miRNA expression. Circular RNAs (CircRNAs), like lncRNAs, affect EZH2 expression via targeting miRNAs. These areas are discussed in the present review with a focus on molecular pathways leading to clinical translation.

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Section: Ezh2 Inhibitors: An Overviewmentioning

confidence: 99%

The long and short non-coding RNAs modulating EZH2 signaling in cancer

et al. 2022

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“…H3K27me3 is closely related to gene silencing, and mutations in the H3K27 methylase EZH2 are widespread in breast cancer, colon cancer, and melanoma [30]. GSK126, a selective histone methylase inhibitor, holds promise for various applications [31]. Zhang et al [32] demonstrated that GSK-126 can enhance the sensitivity of liver cancer cells to other drugs, such as DNMT, epirubicin (EPB), and mitomycin C (MMC).…”

Section: Discussionmentioning

confidence: 99%

GSK-126 Enhances All-Trans-Retinoic Acid (ATRA) Response in Hepatocellular Carcinoma (HCC) by Upregulating RARG Expression

Liu,

Zheng

2024

Discovery Medicine

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Background: Hepatocellular carcinoma (HCC) stands out as one of the most prevalent malignant tumors globally. The combination of all-trans-retinoic acid (ATRA) with FOLFOX chemotherapy has shown promise in enhancing the prognosis of HCC patients. ATRA, serving as a chemosensitizing agent, presents novel possibilities for therapeutic applications. Nevertheless, the responsiveness of HCC cells to ATRA varies. The epigenetic modifier-GSK-126 is currently under investigation as a potential antitumor drug. Our aim is to explore the molecular mechanisms underlying the diverse sensitivity of HCC patients to ATRA, and to propose a new combination regimen. This research aims to lay the groundwork for personalized medication approaches for individuals with HCC. Methods: A cell model with low expression of retinoic acid receptor Alfa (RARA), retinoic acid receptor belta (RARB), and retinoic acid receptor gamma (RARG) was established through siRNA interference. The impact of reduced expression of RARA, RARB, and RARG on the half maximal inhibitory concentration (IC50) of ATRA in Hep3B cells was assessed using the 3-(4,5-Dimethyl-2-Thiazolyl)-2,5-Diphenyl Tetrazolium Bromide (MTT) cytotoxicity assay. Flow cytometry revealed that RARG emerged as the key receptor influencing the combination's sensitivity. Conducting ChIP-qPCR analysis on genomic DNA from HCC cells through relevant websites demonstrated enrichment of the trimethylation modification of lysine 27 on histone H3 (H3K27me3) upstream of the RARG promoter. ChIP-PCR assay confirmed that GSK-126 could diminish H3K27me3 levels on the RARG promoter, subsequently elevating RARG expression. The synergistic efficacy of GSK-126 and ATRA was validated through MTT assay, flow cytometry apoptosis assay, cell cycle assay, and cell scratch assay. Results: Our study unveiled that the insensitivity of HCC cells to ATRA could be linked to the low expression of RARG. ChIP-qPCR analysis illuminated that GSK-126 activated RARG expression by diminishing H3K27me3 enrichment in the RARG promoter region. Consequently, the concurrent administration of ATRA and GSK-126 to hepatoma cells exhibited a synergistic effect, inhibiting cell proliferation, inducing cell apoptosis, and reducing the proportion of cells in the S-phase. Conclusion: Our findings emphasize that the synergistic action of GSK-126 and ATRA enhances the sensitivity of HCC cells by upregulating the expression of RARG. This presents a potential foundation for personalized HCC treatment.

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“…In 2017, the Dana-Farber Cancer Institute disclosed the derivative EZ-53 ( 49 ), which exhibited dual EZH1 and EZH2 inhibitory activities and has a structure similar to those of UNC1999 . Recently, Zhang et al designed and synthesized a series of EZH2 covalent inhibitors that can provide extended pharmacodynamic durations . SKLB-03176 ( 50 ) containing a pyridine piperazine group is the most effective compound.…”

Section: Tazemetostat and Ezh2 Inhibitors In Clinical Trialsmentioning

confidence: 99%

“…75 Recently, Zhang et al designed and synthesized a series of EZH2 covalent inhibitors that can provide extended pharmacodynamic durations. 76 SKLB-03176 (50) containing a pyridine piperazine group is the most effective compound.…”

Section: Tazemetostat and Ezh2 Inhibitors Inmentioning

confidence: 99%

Targeting Enhancer of Zeste Homolog 2 for the Treatment of Hematological Malignancies and Solid Tumors: Candidate Structure–Activity Relationships Insights and Evolution Prospects

Xia

Tian

et al. 2022

J. Med. Chem.

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Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that can change the expression of downstream target genes by catalyzing the trimethylation of lysine 27 of histone H3 (H3K27me3). Studies have found that EZH2 is highly expressed in a variety of tumor tissues and is closely related to the occurrence, development, invasion, and metastasis of tumors; therefore, EZH2 is becoming a new molecular target in antitumor therapy. Tazemetostat (EPZ-6438) was approved in 2020 as the first inhibitor targeting catalytic EZH2 for the treatment of epithelioid sarcoma. In addition, a variety of EZH2 inhibitors are being investigated in basic and clinical research for the treatment of tumors, and encouraging results have been obtained. This article systematically reviews the research progress on EZH2 inhibitors and proteolysis targeting chimera (PROTAC)-based EZH2 degradation agents with a focus on their design strategies, structure− activity relationships (SARs), and safety and clinical manifestations.

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Covalent inhibitors of EZH2: Design, synthesis and evaluation

Cited by 8 publications

References 32 publications

The long and short non-coding RNAs modulating EZH2 signaling in cancer

The long and short non-coding RNAs modulating EZH2 signaling in cancer

GSK-126 Enhances All-Trans-Retinoic Acid (ATRA) Response in Hepatocellular Carcinoma (HCC) by Upregulating RARG Expression

Targeting Enhancer of Zeste Homolog 2 for the Treatment of Hematological Malignancies and Solid Tumors: Candidate Structure–Activity Relationships Insights and Evolution Prospects

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