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Enhancer of zeste homolog 2 (EZH2) inhibitors.

ABSTRACT: Dysregulation of the histone methyltransferase EZH2 plays a critical role in the development of a variety of malignancies including B-cell lymphomas. As a result, a series of small molecule inhibitors of EZH2 have been developed and studied in the pre-clinical setting. Three EZH2 inhibitors: tazemetostat (EPZ-6438), GSK2816126 and CPI-1205 have moved into phase I/phase II clinical trials in patients with non-Hodgkin lymphoma and genetically defined solid tumors. Early data from the tazemetostat trials indicate an acceptable safety profile and early signs of activity in diffuse large B-cell lymphoma and follicular lymphoma, including patients with EZH2 wild-type and mutant tumors. In this review, we present the rationale, key pre-clinical and early clinical findings of small molecule EZH2 inhibitors for use in lymphoma as well as future challenges and potential opportunities for combination therapies.

SUBMITTER: Gulati N

PROVIDER: S-EPMC6659997 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Enhancer of zeste homolog 2 (EZH2) inhibitors.

Gulati Nitya N Béguelin Wendy W Giulino-Roth Lisa L

Leukemia & lymphoma 20180223 7

Dysregulation of the histone methyltransferase EZH2 plays a critical role in the development of a variety of malignancies including B-cell lymphomas. As a result, a series of small molecule inhibitors of EZH2 have been developed and studied in the pre-clinical setting. Three EZH2 inhibitors: tazemetostat (EPZ-6438), GSK2816126 and CPI-1205 have moved into phase I/phase II clinical trials in patients with non-Hodgkin lymphoma and genetically defined solid tumors. Early data from the tazemetostat ...[more]

PMID: 29473431

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Enhancer of Zeste Homolog 2 (EZH2) Mediates Glucolipotoxicity-Induced Apoptosis in ?-Cells.

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Inhibition of enhancer of zeste homolog 2 (EZH2) overcomes enzalutamide resistance in castration-resistant prostate cancer.

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Effects of Enhancer of Zeste Homolog 2 (EZH2) Expression on Brain Glioma Cell Proliferation and Tumorigenesis.

Project description:BACKGROUND Brain glioma is a type of common primary intracranial malignant tumor, the prognosis of which is frequently unfavorable. Enhancer of zeste homolog 2 (EZH2) belongs to poly-sulfur protein family and can mediate cell proliferation and differentiation via the modulation of various genes expressions. In addition, it is further related with occurrence and metastasis of malignant tumors. This study investigated the effect of EZH2 expression on proliferation and tumorigenesis of brain glioma cells. MATERIAL AND METHODS Glioma tumor tissues were collected from 3 patients who received surgery, and the glioma stem cells were then separated, cultured, and identified by flow cytometry. RNA interference approach was used to suppress EZH2 expression, which was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). Clonal formation assay analyzed the change of cell proliferation potency. The effect on tumorigenesis potency of glioma stem cells was determined by mouse transplantation assay. Western blot investigated the effect of EZH2 on levels of oncogenes such as HER-2, c-myc, PI3K, and Akt. RESULTS Flow cytometry revealed cancer stem cells in glioma tissues took up 39.4%, and qRT-PCR showed that EZH2 expression was decreased by 72% after the treatment of RNA interference in glioma cells (P<0.05). Both cell clonal formation and xenograft assays showed that the downregulation of EZH2 inhibited glioma cell proliferation (P<0.05) and weakened tumorigenesis potency (P<0.05). Western blot results showed that the reduction of EZH2 also suppressed expressions of oncogenes including c-myc and Akt (P<0.05). CONCLUSIONS Our data demonstrated that in brain glioma cells, the decrease of EZH2 level could suppress cell proliferation and tumorigenesis potency, and meanwhile inhibit the expressions of oncogenes including c-myc and Akt.

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Novel Natural Inhibitors Targeting Enhancer of Zeste Homolog 2: A Comprehensive Structural Biology Research

Project description:The enhancer of zeste homolog 2 (EZH2) is a methylated modification enzyme of Histone H3-Lys 27. The high expression of EZH2 in cells is closely related to the progression, invasion, and metastasis of neoplasm. Therefore, this target is gradually becoming one of the research hot spots of tumor pathogenesis, and the inhibitors of the EZH2 enzyme are expected to become new antitumor drugs. This study used a series of virtual screening technologies to calculate the affinity between the compounds obtained from the ZINC15 database and the target protein EZH2, the stability of the ligand–receptor complex. This experiment also predicted the toxicity and absorption, distribution, metabolism, and excretion (ADME) properties of the candidate drugs in order to obtain compounds with excellent pharmacological properties. Finally, the ligand–receptor complex under in vivo situation was estimated by molecular dynamics simulation to observe whether the complex could exist steadily in the body. The experimental results showed that the two natural compounds ZINC000004217536 and ZINC000003938642 could bind tightly to EZH2, and the ligand–receptor complex could exist stably in vivo. Moreover, these two compounds were calculated to be nontoxic. They also had a high degree of intestinal absorption and high bioavailability. In vitro experiments confirmed that drug ZINC000003938642 could inhibit the proliferation and migration of osteosarcoma, which could serve as potential lead compounds. Therefore, the discovery of these two natural products had broad prospects in the development of EZH2 inhibitors, providing new clues for the treatment or adjuvant treatment of tumors.

| S-EPMC8560702 | biostudies-literature

Enhancer of zeste homolog 2 (EZH2) regulates adipocyte lipid metabolism independent of adipogenic differentiation: Role of apolipoprotein E.

Project description:Enhancer of zeste homolog 2 (EZH2), an epigenetic regulator that plays a key role in cell differentiation and oncogenesis, was reported to promote adipogenic differentiation in vitro by catalyzing trimethylation of histone 3 lysine 27. However, inhibition of EZH2 induced lipid accumulation in certain cancer and hepatocyte cell lines. To address this discrepancy, we investigated the role of EZH2 in adipogenic differentiation and lipid metabolism using primary human and mouse preadipocytes and adipose-specific EZH2 knockout (KO) mice. We found that the EZH2-selective inhibitor GSK126 induced lipid accumulation in human adipocytes, without altering adipocyte differentiation marker gene expression. Moreover, adipocyte-specific EZH2 KO mice, generated by crossing EZH2 floxed mice with adiponectin-Cre mice, displayed significantly increased body weight, adipose tissue mass, and adipocyte cell size and reduced very low-density lipoprotein (VLDL) levels, as compared with littermate controls. These phenotypic alterations could not be explained by differences in feeding behavior, locomotor activity, metabolic energy expenditure, or adipose lipolysis. In addition, human adipocytes treated with either GSK126 or vehicle exhibited comparable rates of glucose-stimulated triglyceride accumulation and fatty acid uptake. Mechanistically, lipid accumulation induced by GSK126 in adipocytes was lipoprotein-dependent, and EZH2 inhibition or gene deletion promoted lipoprotein-dependent lipid uptake in vitro concomitant with up-regulated apolipoprotein E (ApoE) gene expression. Deletion of ApoE blocked the effects of GSK126 to promote lipoprotein-dependent lipid uptake in murine adipocytes. Collectively, these results indicate that EZH2 inhibition promotes lipoprotein-dependent lipid accumulation via inducing ApoE expression in adipocytes, suggesting a novel mechanism of lipid regulation by EZH2.

| S-EPMC6544862 | biostudies-literature

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