- |||||||||| GSK2816126 / GSK
Targeting EZH2 to overcome chemoresistance in triple negative breast cancers employing combinatorial approach (Hall 1) - Oct 10, 2022 - Abstract #SABCS2022SABCS_655;
Altogether, these results indicated the importance of EZH2 in the regulation of immune functions of trophoblasts and thus highlighted its potential to be explored as a therapeutic target to prevent and treat pregnancy loss. Our data suggest that the combination of GSK126 and Dopamine D1 agonists synergistically inhibits TNBC proliferation by disrupting EZH2 functions leading to necrotic cell death.
- |||||||||| GSK2816126 / GSK
Journal: DNMT and EZH2 inhibitors synergize to activate therapeutic targets in hepatocellular carcinoma. (Pubmed Central) - Oct 7, 2022
Finally, the combination treatment also exacerbates anti-tumor immune responses, while most of these genes were downregulated in over 50% of primary HCC tumors. We have linked the anti-tumor effects of DAC and GSK126 combination treatments to detailed epigenetic alterations in HCC cells, identified potential therapeutic targets and provided a rationale for treatment efficacy for HCC patients.
- |||||||||| GSK2816126 / GSK
Journal: Scutellarin suppresses triple-negative breast cancer metastasis by inhibiting TNFα-induced vascular endothelial barrier breakdown. (Pubmed Central) - Oct 5, 2022
TNFα induced the nuclear translocation of enhancer of zeste homolog-2 (EZH2), and its chemical inhibitor GSK126 blocked TNFα-induced endothelial barrier disruption and subsequent TNBC transendothelial migration...Additionally, SC abrogated the TNFR2-ERK1/2-EZH2 signaling axis both in vivo and in vitro. Our results suggest that SC reduced TNBC metastasis by suppressing TNFα-initiated vascular endothelial barrier breakdown through rescuing the reduced expression of junctional proteins by regulating the TNFR2-ERK1/2-EZH2 signaling pathway.
- |||||||||| GSK2816126 / GSK
Journal: Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor. (Pubmed Central) - Jul 30, 2022
GSK126, a highly selective inhibitor of EZH2 methyltransferase activity influenced H3K27me3 chromatin content and transcriptional control resulting in the expression of core β-cell markers and ductal progenitor genes...These studies show the refractory nature of chromatin characterises exocrine suppression influencing β-cell plasticity. Additional regeneration studies are warranted to determine if the approach of this n-of-1 study generalises to a broader T1D population.
- |||||||||| GSK2816126 / GSK
Preclinical, Journal: Chronic Hypergravity Induces a Modification of Histone H3 Lysine 27 Trimethylation at TCRβ Locus in Murine Thymocytes. (Pubmed Central) - Jul 17, 2022
These experiments showed that the downregulation of H3K27me3 contributes to the regulation of the Vβ germline transcript expression that precedes V(D)J recombination. These data show that modifications of H3K27me3 at the TCRβ locus likely contribute to an explanation of why the TCR repertoire is affected by gravity changes and imply, for the first time, EZH2 in the regulation of the TCRβ locus chromatin structure.
- |||||||||| GSK2816126 / GSK
EZH2 inhibition activates Notch oncosuppressive program in cervical cancer and acute myeloid leukemia cells (Poster Area) - Jun 28, 2022 - Abstract #EACR2022EACR_1188;
Furthermore, the treatment with the pharmacological inhibitor of EZH2; GSK126; synergized with cisplatin at lower doses of both drugs, in impairing proliferation and favoring the death in SiHa and HL-60 cells. Conclusion Overall, our results indicate that EZH2 plays its oncogenic function in CC and AML, at least partially, via Notch repression and suggest EZH2 inhibition as a potential strategy for controlling Notch activation and overcoming cisplatin therapy resistance in tumors in which Notch exerts an oncosuppressive function.
- |||||||||| GSK2816126 / GSK, AZD1390 / AstraZeneca
Journal, BRCA Biomarker, Synthetic lethality: Combined inhibition of EZH2 and ATM is synthetic lethal in BRCA1-deficient breast cancer. (Pubmed Central) - Jun 22, 2022
Taken together, our findings reveal that miR-101/EZH2 negative feedback signaling drives OGD/R-induced injury by activating the MAPK14 signaling pathway in SH-SY5Y cells. Taken together, we identified a synthetic lethal interaction between EZH2 and ATM and propose this synergistic interaction as a novel molecular combination for the treatment of BRCA1-mutant breast cancer.
- |||||||||| GSK2816126 / GSK, Tazverik (tazemetostat) / Epizyme, Eisai
EZH2 INHIBITORS MEDIATE PLATINUM RESISTANCE BY ENHANCED EFFLUX () - May 13, 2022 - Abstract #EHA2022EHA_1699;
This effect was an EZH2-independent off-target effect of chemical EZH2i. Our data do not support the combination of platinum derivates and EZH2i in PTCL.
- |||||||||| GSK2816126 / GSK, thapsigargin / University of Nottingham, Pirbright Institute, GSKJ4 / Yamagata University
Inhibition of the KDM4C and JMJD3 Histone Demethylases Alleviates the Tubular Renal Damage Triggered by Endoplasmic Reticulum Stress (Mini-Orals Hall) - May 5, 2022 - Abstract #ERAEDTA2022ERA_EDTA_1110;
Specific pharmacological inhibitors of the G9a and EZH2 HMTs, BIX-01 294 and GSK126, respectively, and of the JMJD3 and KDM4C HDMs, GSKJ4 and SD-70, respectively, or small interfering RNAs were used...Nat Rev Mol Cell Biol. 2020, 21: 421–438.
- |||||||||| GSK2816126 / GSK
Journal: Activation of FXR and inhibition of EZH2 synergistically inhibit colorectal cancer through cooperatively accelerating FXR nuclear location and upregulating CDX2 expression. (Pubmed Central) - Apr 29, 2022
The combination of FXR agonist OCA plus EZH2 inhibitor GSK126 acted in a synergistic manner across four colon cancer cells, efficiently inhibiting clonogenic growth and invasion in vitro, retarding tumor growth in vivo, preventing the G0/G1 to S phase transition, and inducing caspase-dependent apoptosis...The depletion of CDX2 antagonized the synergistic effects of the drug combination on tumor inhibition. In conclusion, our study demonstrated histone modification-mediated FXR silencing by EZH2 in colorectal tumorigenesis, which offers useful evidence for the clinical use of FXR agonists combined with EZH2 inhibitors in combating CRC.
- |||||||||| GSK2816126 / GSK
Journal: GSK-126 Protects CA1 Neurons from H3K27me3-Mediated Apoptosis in Cerebral Ischemia. (Pubmed Central) - Apr 21, 2022
Further study suggested that the protective role of GSK-126 in ischemic rats was antagonized by U0126, an inhibitor of ERK1/2. Collectively, we demonstrated the potential of H3K27me3 as a novel stroke therapeutic target, and GSK-126 exerted a neuroprotective function in ischemic brain injury, which might be associated with activation of the MAPK/ERK pathway.
- |||||||||| GSK2816126 / GSK, Tazverik (tazemetostat) / Epizyme, Eisai
Biomarker, Journal, Tumor microenvironment: EZH2 Inhibitors Suppress Colorectal Cancer by Regulating Macrophage Polarization in the Tumor Microenvironment. (Pubmed Central) - Apr 19, 2022
Therefore, our data suggested that EZH2i not only suppress CRC cell proliferation directly, but also regulate macrophage by skewing M2 into effector M1 macrophage to exert a tumor suppressive effect. Moreover, our study provided new insight for better understanding of the role of two kinds of EZH2i: EPZ6438 and GSK126, which may pave the way in treating CRC by targeting cancer cells and immune cells via this epigenetic approach in the future.
- |||||||||| oxaliplatin / Generic mfg.
Journal: Downregulation of MEIS1 mediated by ELFN1-AS1/EZH2/DNMT3a axis promotes tumorigenesis and oxaliplatin resistance in colorectal cancer. (Pubmed Central) - Apr 15, 2022
Based on the above, therapeutics targeting the role of MEIS1 in oxaliplatin resistance were developed and our results suggested that the combination of oxaliplatin with either ELFN1-AS1 ASO or EZH2 inhibitor GSK126 could largely suppress tumor growth and reverse oxaliplatin resistance. This study highlights the potential of therapeutics targeting ELFN1-AS1 and EZH2 in cell survival and oxaliplatin resistance, based on their controlling of MEIS1 expression, which deserve further verification as a prospective therapeutic strategy.
- |||||||||| cisplatin / Generic mfg.
Inhibition of EZH2 Action has Contrasting Effects on Ovarian Cancer Stem Cell Populations () - Apr 6, 2022 - Abstract #SRI2022SRI_27;
Together, these data suggest EZH2 disruption of H3K27 trimethylation status negatively impacts the levels of ALDH active cells, but promotes an increase in PROM1 and subsequently CD133 positive cells. However, the combination of GSK-126 with carboplatin or PARPi was sufficient to negate the increase in CD133 positive populations suggesting the combination strategy could reduce CSC populations that contribute to recurrence.
- |||||||||| GSK2816126 / GSK
Journal: TCF3 is epigenetically silenced by EZH2 and DNMT3B and functions as a tumor suppressor in endometrial cancer. (Pubmed Central) - Mar 23, 2022
We show that combined treatment with GSK126 and 5-Aza-2d treatment wit synergistically inhibited methyltransferase activity of EZH2 and DNMT3B, resulting in a profound block of EC cell proliferation as well as EC tumor progression in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. These findings reveal that TCF3 functions as a tumor suppressor epigenetically silenced by EZH2 and DNMT3B in EC, and support the notion that targeting the EZH2/DNMT3B/TCF3/p21 axis may be a novel and effective therapeutic strategy for treatment of EC.
- |||||||||| GSK2816126 / GSK
Journal: TDG is a pig-specific epigenetic regulator with insensitivity to H3K9 and H3K27 demethylation in nuclear transfer embryos. (Pubmed Central) - Mar 15, 2022
More importantly, thymine DNA glycosylase (TDG) was defined as a pig-specific epigenetic regulator for nuclear reprogramming, which was not reactivated by H3K9me3 and H3K27me3 removal. Both combined treatment and transient TDG overexpression promoted DNA demethylation and enhanced the blastocyst-forming rates of SCNT embryos, thus offering valuable methods to increase the cloning efficiency of genome-edited pigs for agricultural and biomedical purposes.
- |||||||||| GSK2816126 / GSK
Chromatin silencing complex EZH2/PRC2 modulates aggressive anaplastic thyroid cancer biology (Section 3) - Mar 9, 2022 - Abstract #AACR2022AACR_5559;
(This work is supported by DOD: W81XWH2010065, for Eswar Shankar) The over-expression and over-activation of EZH2/PRC2 pathway in ATC may contribute to tumor aggressiveness by reducing thyroid cell differentiation and inducing EMT; These results indicate a potential benefit for EZH2 blockage as a neoadjuvant approach to induce differentiation and radioiodine uptake in aggressive thyroid cancer.
- |||||||||| GSK2816126 / GSK, lirametostat (CPI-1205) / MorphoSys
Biomarker, Journal: EZH2 presents a therapeutic target for neuroendocrine tumors of the small intestine. (Pubmed Central) - Feb 1, 2022
Exposure of GOT1 three-dimensional cell spheroids to CPI-1205 or metformin arrested cell proliferation and decreased spheroid size. These novel findings support a possible role of EZH2 as a candidate oncogene in SI-NETs, and suggest that CPI-1205 and metformin should be further evaluated as therapeutic options for patients with SI-NETs.
- |||||||||| Journal, IO biomarker: Development of molecular intervention strategies for B-cell lymphoma. (Pubmed Central) - Jan 14, 2022
Many of these drugs have been approved for clinical use, while several are still under clinical development. Recent studies have identified additional genetic mutations and gene targets for BCL treatment; however, effective molecular interventions targeting these new targets are yet to be developed.
- |||||||||| GSK2816126 / GSK, UNC1999 - University of North Carolina / Chapel Hill
Evaluate the role of EZH1/EZH2 in tumorigenesis of DIPG cells () - Jan 7, 2022 - Abstract #LCC2022LCC_63;
Inhibition of both EZH1/2 resulted in higher antitumor activity than only inhibiting EZH2. Collectively, our research data suggested that targeting both EZH1/2 could provide new therapeutic options for the treatment of PRC2-dependent cancers, like DIPG.
- |||||||||| EZH2 Abundance Regulated by UHRF1/UBE2L6/UBR4 Ubiquitin System is the Potential Therapeutic Target to Trigger Pigmented Phenotype in Melanoma () - Jan 7, 2022 - Abstract #LCC2022LCC_23;
In contrast, EZH2 silencing by siRNA strategy or DZNep, MS1943 that reduces EZH2 protein levels, significantly inhibited cell growth in LPCs by hampering ribosome biogenesis...Proteasomal inhibitor, MG132 treatment induced EZH2 protein levels in HPCs prompted us to look for differentially regulated ubiquitin system proteins in HPC vs LPCs...UBR4 cooperates with UBE2L6 to facilitate this ubiquitination process. Targeting UHRF1/UBE2L6/UBR4 axis can be a better treatment option to trigger HPC state in melanoma in which conventional EZH2 inhibitors are ineffective.
- |||||||||| GSK2816126 / GSK, Tazverik (tazemetostat) / Epizyme, Eisai, Lynparza (olaparib) / Merck (MSD), AstraZeneca
Journal, BRCA Biomarker, PARP Biomarker: Discovery of First-in-Class Dual PARP and EZH2 Inhibitors for Triple-Negative Breast Cancer with Wild-Type BRCA. (Pubmed Central) - Dec 16, 2021
5a can induce autophagy death of tumor cells and cause less damage to normal cells. Therefore, 5a, as a first-in-class dual PARP and EZH2 inhibitor, is a potential anticancer drug candidate for the treatment of TNBC.
- |||||||||| cisplatin / Generic mfg.
Journal: Attenuated expression of SNF5 facilitates progression of bladder cancer via STAT3 activation. (Pubmed Central) - Dec 10, 2021
To the best of our knowledge, the present study, for the first time, showed that low SNF5 expression could promote cell proliferation and migration by activating STAT3 and confer poor prognosis in BC. Importantly, SNF5 expression may be a promising candidate for identifying BC patients who could benefit from EGFR-targeted chemotherapy or cisplatin in combination with EZH2 inhibitor treatment regimens.
- |||||||||| temozolomide / Generic mfg.
Journal: EZH2 regulates the malignancy of human glioblastoma cells via modulation of Twist mRNA stability. (Pubmed Central) - Nov 7, 2021
Further, knockdown of EZH2 or its specific inhibitor GSK126 can decrease expression of Twist, while over expression of Twist can reverse si-EZH2-suppressed malignancy of GBM cells...Collectively, our data suggest that EZH2 might be a potential target for GBM treatment. Further, miR-206/Twist axis is involved in EZH2-regulated malignancy of GBM cells.
- |||||||||| GSK2816126 / GSK
Journal: Combination of BMP2 and EZH2 inhibition to stimulate osteogenesis in a 3D bone reconstruction model. (Pubmed Central) - Oct 20, 2021
Conclusions This study finds that BMP2 and GSK126 co-stimulate osteogenic differentiation of MSCs on 3D scaffolds in vitro and may contribute to enhanced vascularization when implanted in vivo to support bone formation. Thus, epigenetic priming with EZH2 inhibitors may have translational potential in bone healing by permitting a reduction of BMP2 dosing in vivo to mitigate its side effects.
- |||||||||| GSK2816126 / GSK
Journal: EZH2 Inhibition as New Epigenetic Treatment Option for Pancreatic Neuroendocrine Neoplasms (PanNENs). (Pubmed Central) - Oct 14, 2021
Viability of PanNEN cell lines treated with EZH2 inhibitor (GSK126) was determined in vitro...Our results show that EZH2 is highly expressed in high-grade PanNENs, and during disease progression it may contribute to aberrations in the epigenetic cellular landscape. Targeting EZH2 may represent a valuable epigenetic treatment option for patients with PanNEN.
- |||||||||| GSK2816126 / GSK
Journal: The Role of EZH2 Inhibitor, GSK-126, in Seizure Susceptibility. (Pubmed Central) - Oct 6, 2021
Our results suggest that GSK-126 promotes seizure susceptibility due to its role as an EZH2 inhibitor. These findings may provide evidence to support the development of GSK-126 as a clinical drug.
- |||||||||| GSK2816126 / GSK, GSKJ4 / Yamagata University
Preclinical, Journal, Epigenetic controller: Histone H3 Methyltransferase Ezh2 Promotes White Adipocytes but inhibits Brown and Beige Adipocyte Differentiation in Mice. (Pubmed Central) - Sep 19, 2021
The H3K27me3 demethylase Jmjd3/UTX inhibitor GSKJ4 inhibited MEFs' differentiation into brown/beige adipocytes. These results showed that Ezh2 promotes the differentiation of white adipocytes and inhibits the differentiation of brown and beige adipocytes in vivo and in vitro through its methylase activity and this may represent new knowledge for obesity therapeutic strategy.
- |||||||||| metformin / Generic mfg.
Clinical, Journal: Inhibition of EZH2 enhances the antitumor efficacy of metformin in prostate cancer. (Pubmed Central) - Aug 14, 2021
However, GSK126 can inhibit the methyltransferase-dependent interaction between AR and EZH2, thus restoring metformin's efficacy in androgen-refractory PCa cells. Collectively, our finding suggests that the combination of metformin and GSK126 would be an effective approach for future PCa therapy, and particularly effective for AR-positive CRPC.
- |||||||||| ebastine / Generic mfg.
Journal: Antihistamine Drug Ebastine inhibits cancer growth by targeting Polycomb Group Protein EZH2. (Pubmed Central) - Aug 8, 2021
Additionally, ebastine treatment effectively reduced tumor growth and progression, and enhanced progression-free survival in triple-negative breast cancer (TNBC) and drug-resistant castration-resistant prostate cancer (CRPC) patient-derived xenograft (PDX) mice. Our data demonstrated that ebastine is a novel, safe, and potent anticancer agent for patients with advanced cancer by targeting the oncoprotein EZH2.
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