- |||||||||| GSK2816126 / GSK
Journal: EZH2 inhibition induces senescence via ERK1/2 signaling pathway in multiple myeloma. (Pubmed Central) - May 28, 2024
We have previously demonstrated that GSK126, a specific EZH2 inhibitor, exhibits anti-MM therapeutic efficacy and safety in vivo and in vitro; however, its specific mechanism remains unclear...These findings suggest that EZH2 inhibition increases Lamin B1 level and induces senescence by promoting ERK1/2 phosphorylation. These data indicate that EZH2 plays an important role in MM cellular senescence and provide insights into the relationships among Lamin B1, p-ERK1/2, and cellular senescence.
- |||||||||| GSK2816126 / GSK
Journal: Identification and functional analysis of the hub Ferroptosis-Related gene EZH2 in diabetic kidney disease. (Pubmed Central) - May 11, 2024
These data indicate that EZH2 plays an important role in MM cellular senescence and provide insights into the relationships among Lamin B1, p-ERK1/2, and cellular senescence. Overall, our data shouwed that histone H3K27 methyltransferase EZH2 could regulate the renal tubular epithelial cell ferroptosis by suppressing SLC7A11 in DKD, which may serve as a credible reliable indicator for diagnosing DKD and a potential target for treatment.
- |||||||||| trichostatin A (VTR-297) / Vanda, GSK2816126 / GSK
Journal: Inhibition of chromatin condensation disrupts planar cell migration. (Pubmed Central) - Mar 15, 2024
The altered nuclear shape is associated with disrupted cell and nuclear mechanics, suggesting a crucial interplay between chromatin remodeling, nuclear mechanics and migration. These findings shed light on the intricate connection between intranuclear chromatin dynamics, nuclear mechanics, and cell migration, providing a basis for further investigations into the molecular mechanisms governing these processes.
- |||||||||| Nutlin-3 / EMD Serono, GSK2816126 / GSK, Tazverik (tazemetostat) / Eisai, Ipsen
EZH2 INHIBITION PRESERVES GASTRIC PACEMAKER CELL AND GASTRIC MOTOR FUNCTION DURING AGING (Hall A, Poster Hall - Walter E. Washington Convention Center) - Mar 14, 2024 - Abstract #DDW2024DDW_2959;
Similarly, elevated EZH2 and H3K27me3 levels were observed in stomachs of naturally aged mice (22-24 months old) and klotho mice. EPZ6438 treatment prevented the increase in H3K27me3 and the reduction in the expression of the KIT ligand stem cell factor (SCF) by WB and restored gastric ICC decline by IHC.
- |||||||||| cisplatin / Generic mfg.
Mechanism of histone H3K27me3 demethylase therapy for restoring cisplatin sensitivity in refractory testicular cancer (Section 23) - Mar 5, 2024 - Abstract #AACR2024AACR_6717;
Further enrichment and biological classification analysis of these distinct gene subsets are ongoing and will be presented. In summary, our data suggests mechanisms to account for why directly targeting H3K27 methylation with GSKJ4 appear highly effective in treating cisplatin resistant/refractory TGCTs and may provide biomarkers for future clinical investigation of this strategy.
- |||||||||| GSK2816126 / GSK
A universal spike-in normalization strategy for CUT&RUN, CUT&Tag and ATAC-seq (Section 16) - Mar 5, 2024 - Abstract #AACR2024AACR_4315;
In fact, many standard computational pipelines fail to detect a reportedly substantial global H3K27me3 decrease in the presence of GSK126, a therapeutic target for lymphoma and potent inhibitor of the EZH2 methyltransferase...By contrast, these same changes were all missed when omitting the spike-in nuclei. This streamlined spike-in normalization strategy can be easily applied to any number of cells and on a large variety of conditions.
- |||||||||| GSK2816126 / GSK
Attenuating EZH2-mediated metastasis and tumor growth by pharmacological-based approaches using three-dimensional in vitro culture models (Section 22) - Mar 5, 2024 - Abstract #AACR2024AACR_2589;
Here we hypothesize that the presence of dopamine D1 receptor agonist (A77636) enhances the efficacy of EZH2 inhibitors (GSK126) to inhibit in vitro TNBC tumor growth and metastasis...In the microfluidic SynTumor model, circulating tumor cell numbers were reduced by half at 96 hrs after EZH2 combination treatment. Our data indicate that the combinatorial effect of DRD1 agonist and EZH2 inhibitor efficiently attenuates the EZH2-mediated in vitro tumor growth and metastasis.
- |||||||||| GSK2816126 / GSK
Journal, Epigenetic controller: Inhibition of the Histone Methyltransferase EZH2 Induces Vascular Stiffness. (Pubmed Central) - Feb 28, 2024
GSK126 causes vascular stiffening,inducing MMP2 activity, elastin degradation, and modulation of SMC phenotype and cytoskeletal stiffness. These findings suggest that EZH2 inhibitors used to treat cancer could negatively impact the vasculature by enhancing stiffness and merits examination in human trials.
- |||||||||| GSK2816126 / GSK, Zejula (niraparib) / GSK, J&J, Takeda
Review, Journal, BRCA Biomarker, PARP Biomarker, Synthetic lethality: Dual target PARP1/EZH2 inhibitors inducing excessive autophagy and producing synthetic lethality for triple-negative breast cancer therapy. (Pubmed Central) - Jan 17, 2024
and EZH2, and the potential of KWLX-12e also exhibited good antitumor activity with the TGI value of 75.94%, more effective than Niraparib plus GSK126 (TGI
- |||||||||| GSK2816126 / GSK, Tazverik (tazemetostat) / Eisai, Ipsen
Journal: EZH2 inhibitors promote ?-like cell regeneration in young and adult type 1 diabetes donors. (Pubmed Central) - Jan 6, 2024
Reprogrammed pancreatic ductal cells exhibit insulin production and secretion in response to a physiological glucose challenge ex vivo. These pre-clinical studies underscore the potential of small molecule inhibitors as novel modulators of ductal progenitor differentiation and a promising new approach for the restoration of ?-like cell function.
- |||||||||| GSK2816126 / GSK
Journal: LncRNA H19-EZH2 interaction promotes liver fibrosis via reprogramming H3K27me3 profiles. (Pubmed Central) - Dec 4, 2023
Furthermore, treatment with 3-DZNeP or GSK126 significantly inhibited primary HSC activation and proliferation in TGF-?-treated HSCs and H19-overexpreesing LX2 cells in vivo...In conclusion, highly expressed H19 in chronic liver diseases promotes fibrogenesis by reprogramming EZH2-mediated epigenetic regulation of HSCs activation. Targeting the H19-EZH2 interaction may serve as a novel therapeutic approach for liver fibrosis.
- |||||||||| GSK2816126 / GSK
Journal: GSK-126 Attenuates Cell Apoptosis in Ischemic Brain Injury by Modulating the EZH2-H3K27me3-Bcl2l1 Axis. (Pubmed Central) - Nov 22, 2023
The role of H3K27me3 in regulating of the expression of the antiapoptotic molecule B cell lymphoma-2 like 1 (Bcl2l1) explained the antiapoptotic effect of GSK-126. In conclusion, we found that GSK-126 could effectively protect brain cells from apoptosis after cerebral ischemia, and this role of GSK-126 is closely related to an axis that regulates Bcl2l1 expression, beginning with the regulation of EZH2-dependent H3K27me3 modification.
- |||||||||| GSK2816126 / GSK
EZH2 as molecular target for Glioblastoma treatment (X5) - Sep 30, 2023 - Abstract #DGHO2023DGHO_845;
Notably, the monotherapy-induced adoption of a mesenchymal phenotype, accompanied by increased cellular stress, was successfully reversed by the combination. The interaction and activities of the target molecules influence various cellular processes, including cell proliferation, differentiation, and apoptosis.
- |||||||||| GSK2816126 / GSK
Journal: Targeting EZH2 regulates the biological characteristics of glioma stem cells via the Notch1 pathway. (Pubmed Central) - Sep 26, 2023
Additionally, EZH2 is known to regulate the stemness-associated gene expression, proliferation, and invasion ability of GSCs, which may be achieved through the activation of the STAT3 and Notch1 pathways. Furthermore, we demonstrated the effect of the EZH2-specific inhibitor GSK126 on GSCs; these results not only corroborate our hypothesis, but also provide a potential novel treatment approach for glioma.
- |||||||||| 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.
|
