- |||||||||| Journal: UHRF1/UBE2L6/UBR4-mediated ubiquitination regulates EZH2 abundance and thereby melanocytic differentiation phenotypes in melanoma. (Pubmed Central) - Apr 25, 2023
Biochemical assays and animal studies demonstrated that in LPCs, the E2-conjugating enzyme UBE2L6 depletes EZH2 protein in cooperation with UBR4, an E3 ligase, via ubiquitination at EZH2's K381 residue, and is downregulated in LPCs by UHRF1-mediated CpG methylation. Targeting UHRF1/UBE2L6/UBR4-mediated regulation of EZH2 offers potential for modulating the activity of this oncoprotein in contexts in which conventional EZH2 methyltransferase inhibitors are ineffective.
- |||||||||| erastin - Whitehead Institute for Biomedical Research, Dana / Farber Cancer Institute, Columbia University, Prolexys, GSK2816126 / GSK
Clinical implication of EZH2 inhibitors in hepatocellular carcinoma (Section 16; Poster Board #1) - Mar 14, 2023 - Abstract #AACR2023AACR_8377;
EZH2 is a novel suppressor of ferroptosis by negatively regulating lipid metabolism. Thus, our study provides scientific evidence for developing a novel therapeutic strategy for treatment of HCC patients with co-treatment of ferroptosis inducers and EZH2 inhibitors.
- |||||||||| GSK2816126 / GSK
Simultaneous inhibition of EZH2 and activation of dopamine D1 in an isotropic triple-negative breast cancer microgel model (Section 12; Poster Board #12) - Mar 14, 2023 - Abstract #AACR2023AACR_2701;
Tumor spheroids formed after 2 days were subjected to single and combination therapies of GSK126, an EZH2 inhibitor, and A77636, a dopamine agonist over the span of 4 days...Furthermore, knockout of EZH2 in the TNBC cells resulted in inability for tumor spheroid formation and a sensitivity to A77636. Our findings imply that EZH2 is critical for spheroid formation and growth in TNBC and suggest that targeting the EZH2 alongside D1R presents a novel strategy for enhancing EZH2 inhibition
- |||||||||| trichostatin A (VTR-297) / Vanda, GSK2816126 / GSK
Journal: Dose-dependent effects of PRC2 and HDAC inhibitors on cardiomyocyte hypertrophy induced by phenylephrine. (Pubmed Central) - Feb 4, 2023
Ongoing studies will further elucidate this innovative platform for dual hydrophobic drug delivery by assessing the following: dual drug loading and internalization, establishing controlled delivery of the payloads from the nanocarrier system and assessing their synergistic effects. Our data demonstrate diversified effects of TSA and GSK126 on PE-induced cardiomyocyte hypertrophy, and shed light on epigenetic reprogramming in the pathogenesis of cardiac hypertrophy.
- |||||||||| GSK2816126 / GSK
Journal: Changes in Hox Gene Chromatin Organization during Odontogenic Lineage Specification. (Pubmed Central) - Jan 22, 2023
Promoting HOX gene expression in developing teeth using the small molecule EZH2 inhibitor GSK126 resulted in an increased number of patterning events, supernumerary cusp formation, and increased Hoxa4 and Hoxb6 gene expression when compared to the controls. Together, these studies illustrate the profound effects of epigenetic regulatory events at all stages of the differentiation of craniofacial peripheral tissues from the neural crest, including lineage specification, tissue differentiation, and patterning.
- |||||||||| GSK2816126 / GSK
Preclinical, Journal: Effects of prenatal nicotine exposure on enamel formation of offspring mice (Pubmed Central) - Jan 16, 2023
Addition of 10 μmol/L GSK126, could rescue the proliferation activation effect of 1 mmol/L nicotine on DESCs. PNE may delay the process of enamel formation and lineage differentiation, leading to the abnormal proliferation of DESCs and changes of epigenetic modification state in H3K27me3, which affect the development of enamel in offspring mice,suggesting PNE might be one of risk environmental factor for tooth development.
- |||||||||| GSK2816126 / GSK, Tazverik (tazemetostat) / Eisai, Ipsen
Journal: Discovery of IHMT-337 as a potent irreversible EZH2 inhibitor targeting CDK4 transcription for malignancies. (Pubmed Central) - Jan 16, 2023
More significantly, our compound inhibits both DLBCL and TNBC cell proliferation in different preclinical models in vitro and in vivo. Taken together, our findings demonstrate that in addition to enzymatic inhibition, destroying of EZH2 by IHMT-337 could be a promising therapeutic strategy for TNBC and other malignancies that are independent of EZH2 enzymatic activity.
- |||||||||| UHRF1/UBE2L6/UBR4-mediated ubiquitination regulates EZH2 abundance and thereby melanocytic differentiation phenotypes in melanoma () - Jan 13, 2023 - Abstract #LCC2023LCC_75;
In contrast, EZH2 silencing by siRNA or EZH2 protein degradation by DZNep or MS1943 treatment significantly inhibited cell growth in LPCs by hampering ribosome biogenesis...As proteasomal inhibitor MG132 treatment induced EZH2 protein levels in HPCs we explored differentially regulated ubiquitin system proteins in HPC vs LPCs...UBE2L6 has been shown to be downregulated significantly in LPCs by UHRF1-mediated CpG methylation. Targeting this UHRF1/UBE2L6/UBR4 axis may be an optimal method to enforce the HPC state in melanoma in which conventional EZH2 inhibitors are ineffective.
- |||||||||| Preclinical Validation of EZH2 and HDAC I Dual Inhibition As a Potent Therapy for Refractory Myeloid Leukemia Associated with Down Syndrome (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_4073;
Using patient-derived xenograft models of DS-ML, we showed previously that combination of DNA hypomethylating agent azacitidine with HDAC inhibitor panobinostat or BCL2 inhibitor venetoclax showed significant improvement in median survival...The difference in the median survival of the mice treated with the combination was statistically significant when compared to GSK126 or romidepsin (P <0.005)...Further studies to characterize the mechanism of synergy are in progress. In summary, our data show a synergistic effect of EZH2 and HDAC class I inhibition on DS-AML growth and pave the path for clinical evaluation of this combination.
- |||||||||| GSK2816126 / GSK
DNMT AND EZH2 INHIBITORS SYNERGIZE TO ACTIVATE THERAPEUTIC TARGETS IN HEPATOCELLULAR CARCINOMA () - Oct 23, 2022 - Abstract #AASLD2022AASLD_1936;
In summary, our data show a synergistic effect of EZH2 and HDAC class I inhibition on DS-AML growth and pave the path for clinical evaluation of this combination. We have linked the anti-tumor effects of 5-aza-CdR and GSK126 combination treatments to detailed epigenetic alterations in HCC cells, identified potential therapeutic targets and provided a rationale for combination treatment efficacy in HCC patients.
- |||||||||| 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.
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