- |||||||||| GSK2816126 / GSK, Tazverik (tazemetostat) / Epizyme, Eisai
Journal, IO Biomarker: EZH2 inhibitors restore epigenetically silenced CD58 expression in B-cell lymphomas. (Pubmed Central) - Apr 14, 2020
These results indicated that EZH2 is involved in the epigenetic silencing of CD58 in lymphoma cells as a mechanism for tumor immune escape, and EZH2 inhibitors are able to restore epigenetically suppressed CD58 expression. Our findings provide a molecular basis for the combination of an EZH2 inhibitor and immunotherapy for lymphoma treatment.
- |||||||||| GSK2816126 / GSK
Journal: Enhancer of Zeste Homolog 2 (EZH2) regulates adipocyte lipid metabolism independent of adipogenic differentiation: role of apolipoprotein E. (Pubmed Central) - Dec 20, 2019
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 to 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 upregulated 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.
- |||||||||| GSK2816126 / GSK, TAS-117 / Otsuka
Journal: Akt Inhibition Synergizes with PRC2 Inhibition in the Treatment of Multiple Myeloma. (Pubmed Central) - Dec 19, 2019
Moreover, FOXO3 knockdown repressed EZH1 expression. Collectively, the present results unravel some molecular interactions between Akt signaling and epigenetic modulators, which emphasize the benefits of targeting PRC2 full activity and the Akt pathway as a therapeutic option for multiple myeloma.
- |||||||||| Adomet (S-adenosyl-L-methionine) / Abbott, GSK2816126 / GSK, tazemetostat (E7438) / Epizyme, Eisai
Journal, PARP Biomarker: The Antitumoral Effect of the S-Adenosylhomocysteine Hydrolase Inhibitor, 3-Deazaneplanocin A, is Independent of EZH2 but is Correlated with EGFR Downregulation in Chondrosarcomas. (Pubmed Central) - Nov 22, 2019
However, DZNep induces apoptosis in chondrosarcomas in vitro and in vivo, by a mechanism likely mediated though EGFR expression. Consequently, it would be worth initiating clinical trials to evaluating efficiency to S-adenosylhomocysteine hydrolase or EGFR inhibitors in patients with chondrosarcomas.
- |||||||||| GSK2816126 / GSK
INVESTIGATING THE SYNTHETIC LETHALITY OF EZH2 INHIBITION IN ARID1A MUTANT BLADDER CANCER (Grand Ballroom) - Nov 17, 2019 - Abstract #SUO2019SUO_155;
As EZH2 inhibitors are currently in phase I clinical trials with tolerable side effect profiles, these findings warrant further validation and future consideration for therapeutic intervention in early and late stage bladder cancer patients. Future experiments will include further investigation of the candidate genes MTSS1, OPTN, and PTPRR to determine if their induction is sufficient for the GSK-126 sensitivity of ARID1Amut cells.
- |||||||||| GSK2816126 / GSK, TAS-117 / Otsuka
Akt Inhibition Differently Controls PRC2 Components and Synergizes with Dual EZH2/1 Inhibitor in the Treatment of Multiple Myeloma (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_6147;
In conclusion, the present results defined novel signaling-epigenetic crosstalk between PI3K/Akt pathway and PRC2 components, EZH2 and EZH1, and demonstrated that Akt inhibition can differently modulates EZH2 and EZH1 levels via Akt downstream effectors, E2F1 and FOXO3, respectively . Therefore, targeting both EZH2 and EZH1 in addition to Akt inhibition may be a promising rationale to eradicate MM, leading to significant advances in treatment.
- |||||||||| GSK2816126 / GSK
New Insights into PLZF/Rara Mechanism during APL Onset: EZH2 on the Road (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5484;
We also performed EZH2 pharmacological inhibition using GSK126 and UNC1999 on a human cell line expressing the fusion protein PLZF/RARA...CONCLUSION Taken together, our data showed that PLZF/RARA modifies H3K27me3 profiles at enhancer regions and requires EZH2 activity for APL onset . Finally, our results suggest that EZH2 inhibition could be a new promising therapeutic approach for retinoic-acid resistant APL.
- |||||||||| Adomet (S-adenosyl-L-methionine) / Abbott, GSK2816126 / GSK
Journal: An Evolutionarily Conserved Structural Platform for PRC2 Inhibition by a Class of Ezh2 Inhibitors. (Pubmed Central) - Oct 13, 2019
Additional analysis indicated that an evolutionarily conserved structural platform dictates a unique mode of GSK126 binding, suggesting a mechanism of drug selectivity. The existing drug scaffold may thus be used to probe the function and cellular regulation of PRC2 in a wide spectrum of organisms, ranging from fungi to humans.
- |||||||||| GSK2816126 / GSK
EZH2 as a Novel Therapeutic Target for Atrial Fibrosis and Atrial Fibrillation (Zone 1, Science and Technology Hall) - Aug 21, 2019 - Abstract #AHA2019AHA_6212;
Conclusions and implications GSK126 inhibited atrial remodeling and reduced vulnerability to AF by regulating the fibroblasts differentiation through Ang-II-TGF-β-Smads pathway. The present study may provide a novel therapeutic strategy for AF.
- |||||||||| GSK2816126 / GSK, neuroprotectin D1 / Anida Pharma
Journal: Identification of a Chemical Modulator of EZH2-mediated Silencing by Cell-based High-throughput Screening Assay. (Pubmed Central) - Aug 21, 2019
Genome wide expression analysis revealed that after NPD13668 treatment, about half of the upregulated genes overlapped with genes upregulated after treatment with GSK126, well-known EZH2 catalytic inhibitor, indicating that NPD13668 is a potential modulator of EZH2 methyltransferase activity. Our data demonstrated that targeting the pharmacological inhibition of EZH2 activity by NPD13668 might be a novel cancer treatment.
- |||||||||| GSK2816126 / GSK, GSKJ4 / Yamagata University
Journal: TSPYL2 Regulates the Expression of EZH2 Target Genes in Neurons. (Pubmed Central) - Aug 8, 2019
Finally, ChIP showed that hemagglutinin-tagged TSPYL2 co-existed with EZH2 in target promoters in neuroblastoma cells. Taken together, our data suggest that TSPYL2 is recruited to promoters of specific EZH2 target genes in neurons, and enhances their expression for proper neuronal maturation and function.
- |||||||||| GSK2816126 / GSK
Journal: Pharmacological inhibition of EZH2 combined with DNA‑damaging agents interferes with the DNA damage response in MM cells. (Pubmed Central) - Aug 2, 2019
Mechanistically, targeting EZH2 with minimal toxic concentrations of a pharmacological inhibitor (GSK126) markedly weakened the accompanying increase in the histone trimethylation H3K27me3 and aggravated DNA damage response (DDR)‑associated apoptosis in vitro. These data preliminarily confirmed the underlying molecular mechanisms of interaction between histone methylation and the DDR in MM cells, forming the rationale for the combination regimen of EZH2 inhibitors with DNA‑damaging agents for the treatment of MM.
- |||||||||| GSK2816126 / GSK
Journal: Flow-dependent epigenetic regulation of IGFBP5 expression by H3K27me3 contributes to endothelial anti-inflammatory effects. (Pubmed Central) - Jul 13, 2019
Taken together, our findings reveal that atheroprotective flow reduces H3K27me3 as a chromatin-based mechanism to augment the expression of genes that confer an anti-inflammatory response in the endothelium. Our study exemplifies flow-dependent epigenetic regulation of endothelial gene expression, and also suggests that targeting the EZH2/H3K27me3/IGFBP5 pathway may offer novel therapeutics for inflammatory disorders such as atherosclerosis.
- |||||||||| GSK2816126 / GSK, tazemetostat (E7438) / Epizyme, Eisai
Journal: Mechanisms of resistance to EZH2 inhibitors in diffuse large B-cell lymphomas. (Pubmed Central) - May 24, 2019
Notably, EZH2i GSK126 and EPZ-6438-resistant DLBCL cells remained sensitive to the EZH2i UNC1999 and embryonic ectoderm development protein (EED) inhibitor EED226, which provides an opportunity to treat DLBCL that are resistant to these drugs. Collectively, our results underpin the importance for developing a unified approach for forestalling drug resistance by prospectively considering lessons learned from the use of different targeted therapeutic agents.
- |||||||||| GSK2816126 / GSK
Journal: Fibrin glue mediated delivery of bone anabolic reagents to enhance healing of tendon to bone. (Pubmed Central) - May 9, 2019
Histological evaluation confirmed absence of collagen fibers crossing the soft tissue-bone interface indicating immature graft integration as expected at this time point. Our study indicates that hydrogel-mediated delivery of BMP2 and GSK126 appears to be safe and has the potential to enhance tendon-to-bone-tunnel healing in ligament reconstructions.
- |||||||||| GSK2816126 / GSK, tazemetostat (E7438) / Epizyme, Eisai
Journal: Selective targeting of histone modification fails to prevent graft versus host disease after hematopoietic cell transplantation. (Pubmed Central) - Apr 24, 2019
Furthermore, while pharmacologic inhibition of EZH2 by DZNep has been shown to be effective in abrogating mouse GvHD, we found that DZNep was not effective in preventing GvHD in a human T cell xenograft mouse model. Although EZH2 is an attractive target to harness donor allo-reactive T cells in the post-transplant setting to modulate GvHD and the anti-leukemia effect, our results suggest that more selective and effective ways to inhibit EZH2 in human T cells are required.
- |||||||||| GSK2816126 / GSK, Tazverik (tazemetostat) / Epizyme, Eisai, CPI-1205 / Constellation
Journal: Enhancer of zeste homolog 2 (EZH2) inhibitors. (Pubmed Central) - Dec 20, 2018
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.
- |||||||||| luminespib (AUY922) / Ligand, GSK2816126 / GSK
Journal: Hsp90 inhibition destabilizes Ezh2 protein in alloreactive T cells and reduces graft-versus-host disease in mice. (Pubmed Central) - Sep 13, 2017
In contrast, destabilizing T-cell Ezh2 protein by inhibiting Hsp90 using its specific inhibitor AUY922 reduced GVHD in mice undergoing allogeneic HSCT...Importantly, pharmacological inhibition of Hsp90 preserved anti-leukemia activity of donor T cells, leading to improved overall survival of recipient mice after allogeneic HSCT. Our findings identify the Ezh2-Hsp90 interaction as a previously unrecognized mechanism essential for T cell responses and an effective target for controlling GVHD.
- |||||||||| GSK2816126 / GSK
Enrollment change, Trial termination, Trial primary completion date: A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK2816126 in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma, Transformed Follicular Lymphoma, Other Non-Hodgkin's Lymphomas, Solid Tumors and Multiple Myeloma (clinicaltrials.gov) - Jul 31, 2017
P1, N=41, Terminated,
Our findings identify the Ezh2-Hsp90 interaction as a previously unrecognized mechanism essential for T cell responses and an effective target for controlling GVHD. N=169 --> 41 | Recruiting --> Terminated | Trial primary completion date: Jun 2018 --> Jun 2017; The maximal dose and schedule attained with GSK2816126 has shown insufficient evidence of clinical activity, and does not justify further clinical investigation
- |||||||||| GSK2816126 / GSK
Trial primary completion date: A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK2816126 in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma, Transformed Follicular Lymphoma, Other Non-Hodgkin's Lymphomas, Solid Tumors and Multiple Myeloma (clinicaltrials.gov) - May 9, 2017
P1, N=169, Recruiting,
N=169 --> 41 | Recruiting --> Terminated | Trial primary completion date: Jun 2018 --> Jun 2017; The maximal dose and schedule attained with GSK2816126 has shown insufficient evidence of clinical activity, and does not justify further clinical investigation Trial primary completion date: Dec 2017 --> Jun 2018
- |||||||||| GSK2816126 / GSK
Enrollment change, Trial primary completion date: A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK2816126 in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma, Transformed Follicular Lymphoma, Other Non-Hodgkin's Lymphomas, Solid Tumors and Multiple Myeloma (clinicaltrials.gov) - Nov 5, 2015
P1, N=169, Recruiting,
Trial primary completion date: Dec 2017 --> Jun 2018 N=100 --> 169 | Trial primary completion date: Jun 2017 --> Dec 2017
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