GSK2816126 / GSK - LARVOL DELTA

DYRK1A interacts with EZH2 to regulate transcriptionally active chromatin in myeloid leukemia associated with down syndrome (ASH 2025) - "Therefore, we treated cells withEZH2 inhibitor (GSK126) or DYRK1A inhibitor (EHT1610) and performed co-immunoprecipitation...These data indicatethat DYRK1A requires EZH2 for its nuclear localization and likely regulates expression of specific genesrequired for leukemogenesis.Together, these findings suggest that DYRK1A and EZH2 may functionally cooperate to regulate geneexpression at transcriptionally active regions in ML-DS cells, especially within key signal transductionnetworks. This interaction may represent a previously unrecognized mechanism contributing toleukemogenesis in T21, with potential implications for targeting non-canonical EZH2 functions in ML-DS."

Developmental Disorders • Genetic Disorders • Hematological Malignancies • Leukemia • DYRK1A • EZH2 • NTRK

BTK regulates EZH2 stability in myeloid leukemia associated with down syndrome (ASH 2025) - "Although most ML-DS patients respond favorably to chemotherapy, outcomes remainpoor in relapsed or refractory cases, which highlights the need for novel therapeutic strategies.We previously demonstrated that dual inhibition of EZH2 and class I histone deacetylases (HDAC) byusing GSK126 and romidepsin synergistically suppressed ML-DS cell viability (Cicek et al., 2022)...Notably, BTK inhibition by Pirtobrutinib, a FDA-approved reversible BTK inhibitor,recapitulated the effects of combination treatment by reducing EZH2 protein level and inducing celldeath of relapsed ML-DS PDX cells via apoptosis. Proteosome inhibition with MG132 in the presence ofPirtobrutinib rescued EZH2 level, indicating that BTK inhibition reduces EZH2 stability via the ubiquitin-proteasome pathway. Furthermore, BTK inhibition suppressed key E2F-related oncogenic targets,including c-MYC, Bcl-xL and MCL-1, while upregulating the cell cycle inhibitor p21.Together, these findings highlight BTK as a novel..."

Acute Myelogenous Leukemia • Developmental Disorders • Genetic Disorders • Hematological Malignancies • Leukemia • Targeted Protein Degradation • ANXA5 • BCL2L1 • CASP3 • CASP7 • CD34 • GATA1 • MYC • RAD21 • STAG2 • SUZ12

Mechanism of acquired resistance to histone deacetylase inhibitor, romidepsin, in myeloid leukemia associated with down syndrome (ASH 2025) - "In our previous work, we showed that EZH2 inhibitor GSK126, and class I histone deacetylase(HDAC) inhibitor romidepsin, synergistically induced ML-DS cell death (Cicek et al., 2022). RNA-Seq revealed a 4.5-fold increase in ITGB3 TPM, which was confirmed by 8-fold elevated integrin b3 (CD61) protein expression in CMY-R cells. RNA-Seq indicated an upregulation ofCD34 expression in resistant cells, and we confirmed increased CD34, CD44 and CD117 expression inCMY-R cells by flow cytometry, which indicates a shift toward stem-like, adhesion-dependent phenotype.Our findings suggest that resistance to romidepsin in ML-DS involves upregulation of inflammatorysignaling, increased ECM and cell adhesion signaling, and elevated expression of stem cell markers.Targeting inflammatory signaling and/or integrin-mediated adhesion signaling may enhance the efficacyof HDACi and overcome drug resistance in ML-DS and other leukemias."

Epigenetic controller • Preclinical • Developmental Disorders • Genetic Disorders • Hematological Malignancies • Leukemia • Lymphoma • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • CD34 • CD44 • ITGB3 • KIT • STAT1

EZH2 inhibitors enhance the tumor microenvironment by inducing IL-12b secretion in breast cancer cells through NF-κB activation (ESMO Asia 2025) - "Western blotting WB was used to detect the changes in the levels of transcription factors. Exploratory experiments found that the EZH2 inhibitor GSK126 significantly inhibited the growth of EO771 tumors and increased the proportion of CD4+ T lymphocytes in the tumor microenvironment... EZH2 inhibitors initiate the activation of the NF-κB pathway, induce breast cancer cells to upregulate the expression of IL12b, and enhance the recruitment of T cells as well as the infiltration of T lymphocytes within the microenvironment."

Biomarker • Tumor microenvironment • Breast Cancer • Oncology • Solid Tumor • CD4 • IL12B • TCF4

Combinatorial EZH2 Inhibition and Dopamine D1 Agonism Suppresses Pro-Inflammatory Monocytes and TNBC Tumor Progression (SABCS 2025) - "We have previously demonstrated that combined treatment with GSK126, an EZH2 inhibitor and dopamine D1 receptor agonist (A77636) exhibit higher efficacy in inhibiting tumor growth and metastasis of TNBC cells both in vitro and in vivo... These findings demonstrate that dual targeting of EZH2 and A77636 not only suppresses TNBC tumor growth but also reprograms the tumor immune repertoire by shifting monocyte dynamics toward an anti-inflammatory phenotype, offering a promising strategy to overcome resistance and improve therapeutic outcomes. (This work is supported by DOD: W81XWH2010065, for Eswar Shankar)"

Breast Cancer • Oncology • Triple Negative Breast Cancer • EZH2 • IL10 • IL1B

Prevention of cancer initiation by augmenting MHC-I antigen presentation via EZH2 inhibition. (PubMed, Oncogene) - "As EZH2 is highly expressed in numerous precancers, PPT@GSK126 has broad application prospects for reducing these tumor burdens. Schematic images presenting the mechanism of action regarding EZH2 in promoting MT of OLK into HNSCC via inhibiting MHC-I associated APM (left panel) and the proposed therapeutic strategy for preventing OLK carcinogenesis (right panel)."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • B2M • CD8 • EZH2 • GZMB • HLA-B • HLA-C • TAP1

Chronic alcohol intake elicits distinct multi-omic profiles in the liver versus skeletal muscle of mice. (PubMed, bioRxiv) - "Finally, computational drug repurposing identified several compounds for therapeutic targeting of alcohol-induced liver (e.g., saracatinib, GSK126) and muscle (e.g., metformin, trichostatin A) pathophysiology, perhaps working partly to counter metabolic dysregulation. Overall, our study provides a tractable list of therapeutic targets and treatments to help expedite the understanding of and countermeasures against alcohol-related liver disease and alcohol-related myopathy in humans."

Journal • Preclinical • Hepatology • Metabolic Disorders • Myositis

Tui Na Acupressure Modulates Treg Immunosuppression via FoxP3/mTORC1 Signalling in ALS Mice. (PubMed, Immunology) - "Pathway inhibitors (GSK126, rapamycin) reversed these effects, confirming FoxP3/mTORC1 dependency. These findings highlight Tui Na's potential to restore Treg-mediated immune balance in ALS, offering a non-pharmacological therapeutic strategy. This study provides novel immunological insights into Tui Na's mechanisms, advocating its clinical evaluation for ALS and related immune-driven disorders."

Journal • Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders • Inflammation • FOXP3 • IL10 • IL6 • TGFB1 • TNFA

Enhancing Androgen Receptor Antagonist-Mediated Interferon Responses in Prostate Cancer (PCF 2025) - "By integrating RNA-seq and ChIP-seq (AR and H3K27Ac) data in VCaP cells, we found that AR binding sites are generally not associated with genes upregulated by AR inhibition using enzalutamide (Enz), suggesting indirect or epigenetically mediated repression...Treatment with the DNA methyltransferase inhibitor decitabine (DAC) upregulated ~55% of genes induced by Enz, while inhibition of H3K27 methylation via EZH2 inhibitor (GSK126) had a limited effect, underscoring the dominant role of DNA methylation in silencing EREs...Finally, co- treatment with Enz and birinapant, a SMAC mimetic that activates both canonical and non-canonical NF-κB signaling, produced a marked increase in HLA class I expression...• Prostate Cancer Foundation Young Investigator Award • Career Enhancement Program Awards (NIH/Dana-Farber/Harvard Cancer Center SPORE in Prostate Cancer) • BIDMC Philanthropy Pilot Award Conflicts of Interest Disclosure Statement. No conflicts of interest"

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ADAR • AR

THE EZH2 INHIBITOR GSK126 SYNERGIZES WITH CHOLESTEROL-LOWERING STATINS TO BLOCK AGRESSIVE HEPATOBLASTOMA (SIOP 2025) - "Background and Aimes Background: Hepatoblastoma (HB) is a pediatric liver cancer characterized by Wnt signaling activation. Collectively, our data demonstrate the oncogenic function of EZH2 in HB through its histone methyltransferase activity and the therapeutic benefit of combining a blocker of EZH2 methyltransferase activity and an inhibitor of cholesterol synthesis."

Hepatoblastoma • Liver Cancer • Pediatrics • Solid Tumor • DUSP5 • DUSP9 • EZH2

Epigenetic reprogramming via EZH2 inhibition rescues fibroadipose pathogenesis in secondary lymphedema through activating PPARγ signaling. (PubMed, J Orthop Translat) - "EZH2 inhibitors (EPZ6438, GSK126) were intraperitoneally injected. EZH2 inhibitors exerted potent anti-fibrotic effects in secondary lymphedema though activating PPARγ signaling, offering novel insights and strategies for fibrotic disorders. This study demonstrated that targeted inhibition of the EZH2-PPARγ axis effectively inhibited fibrogenic differentiation of AdMSCs and reduced fibroadipose tissue in secondary lymphedema, indicating it is a promising strategy for secondary lymphedema treatment, offering novel insights and strategy for musculoskeletal fibrotic disorders."

Journal • Fibrosis • Musculoskeletal Diseases • PPARG • TGFB1

The EZH2 Inhibitor GSK126 Alleviates Thromboinflammation in Deep Vein Thrombosis by Suppressing TLR4 Signaling via H3K27me3 Modulation. (PubMed, J Inflamm Res) - "In vitro, human umbilical vein endothelial cells (HUVECs) were stimulated with lipopolysaccharide (LPS) and treated with GSK126, either alone or in combination with the TLR4-specific inhibitor TAK-242. These findings suggest that GSK126 alleviates TLR4-mediated inflammation, likely through its modulation of histone methylation, specifically H3K27me3. Our results support a role for TLR4 signaling in DVT pathogenesis and suggest that EZH2 inhibition with GSK126 may represent a novel therapeutic approach to thromboinflammation by modulating H3K27me3 and suppressing TLR4-driven inflammatory pathways."

IO biomarker • Journal • Cardiovascular • Hematological Disorders • Inflammation • Thrombosis • Venous Thromboembolism • NFKBIA

Epigenetic mechanism of EZH2-mediated BACH2 regulation in the pathogenesis of Hashimoto's thyroiditis (ATA 2025) - "The EZH2 inhibitor GSK126 significantly alleviated thyroid inflammation in SAT mice. EZH2 upregulates BACH2 expression through H3K27me3, potentially further promoting the secretion of autoimmune IgG by B cells in the thyroid, thereby contributing to the pathogenesis of HT. These findings suggest that EZH2 may serve as a novel therapeutic target for HT."

Late-breaking abstract • Endocrine Disorders • Immunology • Inflammation • BACH2 • EZH2

Notch activation downregulates EZH2 to thereby attenuate endothelial cell proliferation and angiogenesis via MYC destabilization. (PubMed, Life Sci) - "Our findings not only elucidate the novel role of EZH2 in mediating Notch function in angiogenesis but also provide a promising therapeutic strategy for treating neovascularization-related diseases with EZH2 inhibitors."

Journal • Retinal Disorders • CDH5 • EZH2 • MYC

USP44 promotes chemotherapeutic drug resistance of triple negative breast cancer through EZH2 protein stability. (PubMed, Cancer Biol Ther) - "Notably, treatment with GSK126, a specific EZH2 inhibitor, reversed the chemoresistance induced by USP44 overexpression. USP44/EZH2 signaling pathway is one of the key to causing the drug resistance of TNBC, warranting further clinical investigation."

Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • Triple Negative Breast Cancer • EZH2 • USP44

Combined therapy targeting AR and EZH2 restrains the growth of castration resistant prostate cancer by enhancing antitumor T cell response (EACR 2025) - "These results promote the combined use of enzalutamide and GSK-126 to restrain CRPC growth and NEPC differentiation, and, simultaneously, to awake antitumor T cell response, opening new possibilities for immunotherapy in prostate cancer."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD4 • CD8 • IFNG • IL17A

Epigenetic Regulation to Improve Regeneration of Glucose-Responsive Β-Like Cells (IPITA 2025) - " Human pancreatic ductal cells and fractionated exocrine cells (n=3, from T1D and non-diabetic donors) were transiently exposed to EZH2 inhibitors, GSK126 and Tazemetostat. These findings highlight the regenerative potential of pancreatic progenitor cells and the role of EZH2 inhibition in facilitating differentiation into β-like insulin-secreting cells. The use of human donor tissues through Islet Isolation and Transplantation Programmes provides a physiologically relevant platform for β-cell regeneration, enhancing the translational potential of cell-based diabetes therapies. This study underscores the importance of epigenetic regulation as a novel approach to β-cell regeneration and diabetes treatment."

Immunology • Metabolic Disorders • Type 1 Diabetes Mellitus • PDX1

Hyperoxia Induced Alteration of Chromatin Structure in Human Bone Marrow Derived Primary Mesenchymal Stromal Cells. (PubMed, Adv Biol (Weinh)) - "Epigenetic modifications and DNA damage under hyperoxia is investigated, which is also found to be affected by the pretreatment of GSK126. The techniques and discoveries provide mechanistic insights into chromatin remodeling, potentially paving the way for novel therapeutic strategies to combat genotoxic oxidative stress-commonly associated with degenerative diseases and aging-and to enhance cell-based therapies in regenerative medicine."

Journal

SALL1 is essential for Histone H3K27 methyltransferase EZH2 to regulates apoptotic responses in renal ischemia/reperfusion injury (ERA 2025) - "The study further reversed the effects of EZH2 silencing by silencing SALL1 or administering the Wnt/β-catenin inhibitor icg001...Finally, the study showed that the EZH2 inhibitor GSK-126 significantly alleviated ischemia/reperfusion-induced AKI. 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

Nano particle loaded EZH2 inhibitors: Increased efficiency and reduced toxicity for malignant solid tumors. (PubMed, J Transl Int Med) - "Additionally, GSK126 NPs can partially counteract the effects of GSK126 on MDSCs, particularly by decreasing the infiltration of M-MDSCs into tumors. Albumin-based EZH2i NPs have potent anti-cancer efficacy with tolerable adverse effects, providing promising opportunity for future clinical translation in treating solid tumors."

Journal • Oncology • Solid Tumor • EZH2

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

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

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