GSK2816126 / GSK - LARVOL DELTA

EZH2 inhibitor and Vismodegib synergistically inhibit the growth and metastasis of medulloblastoma. (PubMed, Med Oncol) - "This synergy was further confirmed by SynergyFinder analysis, which revealed a remarkable highest single-agent score of 14.85 for the GSK126 and Vismodegib combination. Importantly, the enhanced efficacy of the combined EZH2i and Vismodegib therapy in suppressing tumor growth was also verified by the xenograft experiments in vivo. In summary, the combined use of EZH2i and Vismodegib demonstrated a remarkable synergistic effect in suppressing MB growth, presenting a promising treatment option for MB patients who had become resistant to Vismodegib."

Journal • Brain Cancer • Medulloblastoma • Oncology • Solid Tumor

Validation of an LC-MS/MS Method for the Simultaneous Intracellular Quantification of the CDK4/6 Inhibitor Abemaciclib and the EZH2 Inhibitors GSK126 and Tazemetostat. (PubMed, Pharmaceutics) - " In conclusion, the observed synergistic antitumor effect could be partly due to increased intracellular accumulation, although this alone is certainly not sufficient to explain it. Overall, the developed method provides a valuable approach for characterizing interactions at the transport level and for predicting the efficiency of both anticancer substance classes in different cell lines."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • ABCB1 • ABCG2

Enhancer of zeste homolog 1/2 dual inhibitor valemetostat outperforms enhancer of zeste homolog 2-selective inhibitors in reactivating latent HIV-1 reservoirs ex vivo. (PubMed, Front Microbiol) - "ACH2 cells were treated with valemetostat for 7-14 days and with suberoylanilide hydroxamic acid (SAHA)...Valemetostat reversed latently HIV-l-infected CD4+ T cells isolated from patients with HIV-1 and induced HIV-1 mRNA expression more potently than GSK126 and E7438...Kyoto Encyclopedia of Genes and Genomes enrichment pathway analysis showed that these 21 hub genes contributed to various signaling pathways, including the JAK-STAT signaling pathway. This study provides novel insights for the development of treatments to reactivate latently HIV-1-infected cells."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease • CD4 • EZH2

Epigenetic drivers of enzalutamide resistance in prostate cancer: targeting of DNMTs and EZH2 as therapeutic strategies to overcome enzalutamide resistance in prostate cancer (AACR 2025) - "Where indicated DNMTi (5-AZA-dC) and EZH2i (GSK-126 ) and Enz were used at 5uM concentrations. Overall, our findings reveal that the DNA and histone methylation pathways play an important role in prostate cancer and development of ENZ-Resistance, and that targeting these epigenetic regulators by small molecule inhibitors, may help overcome therapy resistance in PCa.Supported in part by: Funds from VA Merit Award: I01BX005351, NIH/NCI RO1: CA242839, and LSUHSC, NOLA."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CHGA • EZH2 • KRT18 • KRT18 • SPDEF

Dual epigenetic targeting of hepatocellular carcinoma (AACR 2025) - "Patients with high expression levels of both EZH2 and LSD1 exhibit the poorest survival, suggesting that dual inhibition of these enzymes may offer a more effective therapeutic strategy than monotherapy in HCC.Dual inhibition of EZH2 and LSD1 using GSK126 (an EZH2 inhibitor) and SP2509 (an LSD1 inhibitor) more effectively suppresses liver cancer cell proliferation compared to single-agent treatments. Although EZH2 and LSD1 inhibitors are currently undergoing clinical trials for various cancers, their combination has not yet been explored in HCC. Therefore, evaluating this dual epigenetic therapy for HCC treatment represents a promising direction for future research with immediate translational potential."

Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • CCND1 • EZH2 • KDM1A • PCNA

Synergistic inhibition of TNBC via enhancer of zeste homologue 2 (EZH2) inhibition and D1 receptor agonism (AACR 2025) - "GSK126 and A77636 treatment in combination significantly reduced tumor volume and decreased EZH2 expression in monocytes and neutrophils within the blood and tumor microenvironment and lowering the levels of pro-inflammatory cytokine IL-1β. In summary, this approach unveils new possibilities for treating TNBC by concurrently targeting EZH2 and DRD1 through a combinatorial strategy."

IO biomarker • Breast Cancer • Hematological Malignancies • Oncology • Solid Tumor • Triple Negative Breast Cancer • EZH2 • IFNG • IL1B • PD-L1

The mechanism of EZH2/H3K27me3 downregulating CXCL10 to affect CD8+ T cell exhaustion to participate in the transformation from myelodysplastic syndrome to acute myeloid leukaemia. (PubMed, Br J Haematol) - "NHD13 mice were treated with GSK126 (EZH2 inhibitor) and CXCL10 neutralizing antibody, with transformation time, blood cell counts and CD8+ T cell determined...EZH2-mediated H3K27me3 curbed CXCL10 transcription and secretion. Collectively, EZH2/H3K27me3 downregulates CXCL10 to facilitate CD8+ T-cell exhaustion, accelerating transformation from MDS to AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • CD8 • CXCL10 • EZH2

Dual targeting of CXCR4 and EZH2 in endometriosis. (PubMed, iScience) - "CXCR4 inhibitor, AMD3100, decreased the PF-induced expression of these factors and reduced migration, but increased the proliferation of hESCs. In contrast, the EZH2 inhibitor, GSK126, decreased the expression of EZH2 and H3K27me3 and reduced proliferation, but increased the expression of CXCR4 and migration of hESCs. A combination of both inhibitors decreased the expression of CXCR4, EZH2, and H3K27me3, as well as reduced cell proliferation and migration. Our study suggests that targeting both CXCR4 (inflammation) and EZH2 (epigenetics) may be a better alternative for women with endometriosis."

Journal • Endometriosis • Gynecology • Inflammation • Women's Health • CXCR4 • EZH2

Paternal DEHP Exposure Triggers Reproductive Toxicity in Offspring via Epigenetic Modification of H3K27me3. (PubMed, Toxics) - "Additionally, the down-regulation of Bcl-2 can be reversed by treatment with the H3K27me3 inhibitor GSK126. To conclude, DEHP leads to transgenerational harm to male offspring reproductive systems, with the epigenetic mechanism of H3K27me3 playing a key role in mediating these effects."

IO biomarker • Journal • BCL2

Enhanced mitochondrial function and delivery from adipose-derived stem cell spheres via the EZH2-H3K27me3-PPARγ pathway for advanced therapy. (PubMed, Stem Cell Res Ther) - "Enhancing mitochondrial ATP production via the EZH2-H3K27me3-PPARγ pathway offers an alternative strategy to conventional cell-based therapies. High-functional mitochondria and delivery efficiency show significant potential for regenerative medicine applications."

Journal • PPARG • TNFA

Unveiling the effects of GSK126 on osteosarcoma cells implications for apoptosis, autophagy, and cellular migration. (PubMed, Discov Oncol) - "Our findings revealed that GSK126 induced apoptosis and autophagy, evidenced by increased markers like cleaved caspase-3 and LC3-II, and decreased cellular migration, through downregulation of the Fuse Binding Protein 1 (FBP1)/C-Myc axis. These findings suggest GSK126 as a promising therapeutic against osteosarcoma, offering a dual action of promoting cell death and hindering migration."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CASP3 • MYC

EZH2-mediated macrophage-to-myofibroblast transition contributes to calcium oxalate crystal-induced kidney fibrosis. (PubMed, Commun Biol) - "Clodronate liposome (CLO)-mediated macrophage depletion attenuates fibrosis in male nephrocalcinosis mice...Ezh2 inducible knock-out or inhibition by GSK-126 attenuates MMT and renal fibrosis...The Co-IP and molecular docking analysis shows that DUSP23 mediates the dephosphorylation of pSMAD3 (Ser423/425). Thus, our study found that EZH2 promotes kidney fibrosis by meditating MMT via the DUSP23/SMAD3 pathway in nephrocalcinosis."

Journal • Chronic Kidney Disease • Fibrosis • Immunology • Metabolic Disorders • Nephrology • Renal Disease • DUSP23 • EZH2 • SMAD3

Marek's disease virus-encoded microRNA-M6-5p facilitates viral latent infection by targeting histone demethylase KDM2B. (PubMed, J Virol) - "Furthermore, KDM2B knockdown increased the level of the transcriptionally repressive histone mark H3K27me3 on the key lytic gene pp38 promoter, accompanied by suppression of pp38 expression and reduced latent-to-lytic switch in MDV-latently infected cells, while treatment of cells with H3K27me3 inhibitors (GSK126 and Tazemetostat) markedly promoted the expression of pp38 and MDV reactivation from latency. Mechanistically, miR-M6-5p epigenetically suppressed the expression of the viral lytic gene pp38 by directly targeting the histone demethylase KDM2B. These findings will advance our understanding of the role of virus-encoded miRNA in the regulation of viral latency and will help guide the development of novel strategies for the effective control of MDV."

Journal • Infectious Disease • Oncology • CD4

APN/AdipoRon regulates luteal steroidogenesis through AMPK/EZH2/H3K27me3 in goats. (PubMed, J Steroid Biochem Mol Biol) - "The increased H3K27me3 expression and decreased steroidogenic protein (CYP11A1 and HSD3B) expression after GSK126 (EZH2 inhibitor) treatment were consistent with the effects seen after AdipoRon treatment. In conclusion, APN/AdipoRon inhibits luteal steroidogenesis by inhibiting the interaction between AMPK and EZH2, thereby promoting H3K27me3 expression."

Journal • AMPK • EZH2

Enhancer of zeste homologue 2 (EZH2) inhibition in Triple Negative Breast Cancer (TNBC) attenuates tumor growth in vitro and in vivo altering the tumor immune microenvironment. (SABCS 2024) - "We hypothesize that combined treatment of dopamine D1 receptor agonist (A77636) and EZH2 inhibitors (GSK126) inhibits tumor growth and metastasis of TNBC cells both in vitro and in vivo... Our data indicate that the combinatorial effect of DRD1 agonist and EZH2 inhibitor efficiently attenuates the EZH2-mediated tumor growth and innate immune environment in TNBC."

IO biomarker • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • EZH2 • IFNG • PD-L1

Identification of ETV5 as a prognostic marker related to epigenetic modification in pan-cancer and facilitates tumor progression in hepatocellular carcinoma. (PubMed, Sci Rep) - "Our further experiments evidences indicated that ETV5 facilitated cell proliferation and reduced sensitivity to GSK126 via regulating EZH2. Collectively, this study comprehensively elucidates the carcinogenic effects and molecular mechanisms of ETV5 in tumorigenesis and development, and provides theoretical basis and guidance for tumor diagnosis, targeted therapy for ETV5 and clinical epigenetic drug research."

Biomarker • Journal • Pan tumor • Hepatocellular Cancer • Oncology • Solid Tumor • ETV5

An Epigenetic Drug, GSK126 Mitigates Endothelial to Mesenchymal Transition Attenuating Atherosclerosis in Diabetes (AHA 2024) - "The study identified EZH2 inhibition as a novel therapeutic target in diabetes induced EndMT in atherosclerosis. These findings highlighted ongoing efforts to develop targeted therapies for diabetic patients who are at risk to develop cardiovascular disease."

Atherosclerosis • Cardiovascular • Diabetes • Dyslipidemia • Metabolic Disorders • APOE • MMP2 • NOS3 • TNFA

Refractory testicular germ cell tumors are highly sensitive to the targeting of polycomb pathway demethylases KDM6A and KDM6B. (PubMed, Cell Commun Signal) - "While GSK-J4 had minimal effects alone on TGCT tumor growth in vivo, it dramatically sensitized cisplatin-sensitive and -resistant TGCTs to cisplatin...Further, several chromatin modifier genes, including BRD4, lysine demethylases, chromodomain helicase DNA binding proteins, and lysine methyltransferases, were repressed with cisplatin only in KDM6A/KDM6B-targeted cells, implying that KDM6A/KDM6B inhibition sets the stage for extensive chromatin remodeling of TGCT cells upon cisplatin treatment. Our findings demonstrate that targeting polycomb demethylases is a new potent pharmacologic strategy for treating cisplatin resistant TGCTs that warrants clinical development."

Journal • Genito-urinary Cancer • Germ Cell Tumors • Oncology • Solid Tumor • Testicular Cancer • BRD4 • KDM6A • KDM6B

SALL1 Is Essential for Histone H3K27 Methyltransferase EZH2 to Regulate Apoptotic Responses in Kidney Ischemia-Reperfusion Injury (KIDNEY WEEK 2024) - "The study further reversed the effects of EZH2 silencing by silencing SALL1 or administering the Wnt/β-catenin inhibitor icg001. Our results indicate that silencing EZH2 can protect renal function by relieving transcriptional inhibition of SALL1, activating the Wnt/β-catenin pathway, and attenuating tubular epithelial apoptosis response. These results highlight the potential therapeutic value of targeting EZH2 in ischemia/reperfusion-induced AKI."

Acute Kidney Injury • Cardiovascular • Nephrology • Renal Disease • Reperfusion Injury • EZH2

EZH2 inhibition or genetic ablation suppresses cyst growth in autosomal dominant polycystic kidney disease. (PubMed, J Transl Med) - "Our findings elucidate the pivotal role of EZH2 in promoting renal cyst growth through epigenetic mechanisms and suggest that EZH2 inhibition or ablation may serve as a novel therapeutic approach for managing ADPKD."

Journal • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • CDKN1A • EZH2 • GPX4 • PKD1 • PRKD1 • SLC7A11

Synergistic antitumor effects in glioblastoma through selective modulation of epigenetics and the cell cycle (DGHO 2024) - "We have effectively targeted two key hallmarks of GBM: epigenetic alterations and cell cycle dysregulation. THZ-1 induces cell cycle arrest and GSK126 induces differentiation. The combination of both agents synergistically enhanced antitumor effects in clinically relevant 2D and 3D models via induction of apoptosis, inhibition of cell growth and invasion."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CDK7

HISTONE H3 METHYLTRANSFERASE AS PROMISING TARGET IN HIGH-RISK HEPATOBLASTOMA (SIOP 2024) - "Conclusion, : Adding Histone H3 methyltransferase inhibitor (EZH2 inhibitor) to the treatment regimen of high-risk HB could potentially improve outcomes."

Epigenetic controller • Gastrointestinal Cancer • Hepatoblastoma • Hepatology • Liver Cancer • Oncology • Pediatrics • Solid Tumor • NSD2

Combined inhibition of EZH2 and CDK4/6 perturbs endoplasmic reticulum-mitochondrial homeostasis and increases antitumor activity against glioblastoma. (PubMed, NPJ Precis Oncol) - "He, we show that combined use of the EZH2 inhibitor GSK126 and the CDK4/6 inhibitor abemaciclib synergistically enhances antitumoral effects in preclinical GBM models. Mechanistically, this was due to transcriptional changes in genes involved in mitotic aberrations/spindle assembly (Rb, PLK1, RRM2, PRC1, CENPF, TPX2), histone modification (HIST1H1B, HIST1H3G), DNA damage/replication stress events (TOP2A, ATF4), immuno-oncology (DEPDC1), EMT-counterregulation (PCDH1) and a shift in the stemness profile towards a more differentiated state. We propose a dual EZH2/CDK4/6 blockade for further investigation."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • ATF4 • CALR • CDK4 • DEPDC1 • HIF1A • PLK1 • RRM2 • TOP2A

EZH2-H3K27me3-Mediated Epigenetic Silencing of DKK1 Induces Nucleus Pulposus Cell Pyroptosis in Intervertebral Disc Degeneration by Activating NLRP3 and NAIP/NLRC4. (PubMed, Inflammation) - "Additionally, the epigenetic regulation of DKK1 by EZH2 was explored in NP cells treated with the EZH2 inhibitors GSK126/DZNep...EZH2 negatively regulates DKK1 expression via H3K27me3 methylation, promoting NP cell pyroptosis in IDD patients. This regulatory effect involves the activation of NLRP3 and NAIP/NLRC4 inflammasomes."

Journal • DKK1 • EZH2 • IL1B • NLRP3

Modeling castration resistance in GEMMs identify Nsd2 as a target of AR sensitivity (EACR 2024) - "Moreover, preclinical anti-Ezh2 drugs (GSK126) treatment was tested on NPp53NEK GEM models.Results and Discussions Our data demonstrated that Nsd2 gain of function results in shorter latency and enhanced aggressiveness in the NPp53 CRPC model but not in the castration sensitive PC (CSPC) NP model...Finally, gene expression and transcriptional regulation analysis demonstrated that Nsd2 overexpression shapes the AR cistrome in CRPC.Conclusion In short, Nsd2 overexpression cooperates with AR to drive CRPC and resistance to anti-androgen therapies, and mainly via favoring cell plasticity. Moreover, the data generated in this study suggest new therapeutic opportunities for combination treatments with epigenetic drugs to re-sensitize CRPC to anti-androgen."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • NSD2