GSK2816126 / GSK - LARVOL DELTA

Cannabidiol alters the epigenome of hormone-dependent prostate cancer cells. (PubMed, Biomed Pharmacother) - "CBD exerts anti-cancer effects in prostate cancer, potentially through disruption of cell cycle regulation and epigenetic modulation. These findings support its potential as a therapeutic agent, particularly in combination with targeted treatments."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CDK1 • DNMT1 • EZH2

In vivo labeling-based proteomic analysis of early follicle oocytes and cisplatin-induced alterations in mice. (PubMed, Nat Commun) - "Notably, simultaneous application of cisplatin and EZH2's inhibitor, GSK126, relieved cisplatin-induced oocyte developmental defects. Our study provides a systematic proteomic characterization of oocytes predominantly from primordial follicles in female mice, and reveals dynamic proteome shifts in response to chemotherapeutic agents, laying the foundation for targeted fertility-preserving strategies."

Journal • Preclinical

Epigenetic reduction OF H3K9me3 and H3K27me3 by RK-701 and GSK 126 improves the developmental competence of bovine SCNT embryos. (PubMed, Theriogenology) - "Overall, this approach effectively reduced repressive histone marks, enhanced epigenetic reprogramming, and improved ZGA, thereby increasing the developmental rate and adhesion potential of bovine SCNT embryos. These findings suggest that combined treatment with RK-701 and GSK-126 may provide a simple and practical strategy for improving the efficiency of bovine cloning."

Journal

Nicotinamide N-methyltransferase deficiency disrupts endometrial decidualization partly through dysregulated H3K27 trimethylation in recurrent implantation failure. (PubMed, Mol Cell Endocrinol) - "Embryo implantation critically depends on the establishment of endometrial receptivity, which is governed by progesterone-driven stromal decidualization during the mid-secretory phase...Pharmacologic inhibition of histone methylation by 3-deazaneplanocin A or selective EZH2 inhibition by GSK126 partially rescued both molecular and morphological defects in NNMT-deficient stromal cells. In vivo, uterine NNMT silencing in pregnant mice also increased H3K27me3 level, reduced the expression of decidualization-related genes, and decreased the number of implantation sites. Collectively, our findings identify NNMT as a metabolic-epigenetic regulator of endometrial receptivity, and support its potential as a candidate biomarker for RIF."

Journal • IGFBP1 • NNMT • PRL

Chromobox 4 interacts with pregnane X receptor to repress CYP3A4 expression through polycomb repressive complex 1/2-mediated epigenetic regulation. (PubMed, Drug Metab Dispos) - "Treatment with GSK126, an EZH2 inhibitor, significantly increased CYP3A4 mRNA and protein levels in HepaSH cells and ShP51 cells...Consistently, CBX4 knockdown enhanced rifampicin-induced CYP3A4 expression, whereas its overexpression attenuated this induction...The findings demonstrate that CBX4 interacts with PXR and binds to the CYP3A4 regulatory regions, where it recognizes enhancer of zeste homolog 2-mediated trimethylation of lysine 27 on histone H3 and represses CYP3A4 transcription via chromatin condensation. Given the increasing clinical interest in CBX inhibitors for cancer therapy, these findings highlight a potential risk of drug-drug interactions associated with CBX4 inhibition."

Journal • Oncology • CYP3A4 • EZH2

Enhancer of zeste homolog 2 regulates B-cell responses in a NOD.H-2h4 model of spontaneous autoimmune thyroiditis. (PubMed, Endocrinology) - "EZH2 contributes to B cell-mediated immune responses and IgG production through epigenetic mechanisms in SAT. BACH2 may represent one downstream target of EZH2, but additional pathways are likely involved."

Journal • Endocrine Disorders • Immunology • Inflammation • BACH2

Histone methyltransferase inhibitors prevent lens opacity in diabetic cataract rats. (PubMed, Biochim Biophys Acta Gen Subj) - "Histone methyltransferases are involved in lens opacity in DC rats by regulating Pikfyve gene expression."

Journal • Preclinical • Cataract • Ophthalmology • H19 • PTH1R • TNFA

Robust high-throughput screening platform for H3K27me3 inhibition; compatible with non-small molecule candidates | Poster Board #1105 (ACS-Fall 2026) - "We validated our methodology using established inhibitors and a suite of newly designed peptides targeting PRC2 components. Specifically, the IC50 value of the known inhibitor GSK126 obtained using this assay was consistent with values reported in existing literature, confirming the reliability and accuracy of our platform for characterizing hydrophobic and peptide-based inhibitors"

Genito-urinary Cancer • Hematological Malignancies • Lymphoma • Non Small Cell Lung Cancer • Ovarian Cancer • Prostate Cancer • Solid Tumor

Robust high-throughput screening platform for H3K27me3 inhibition; compatible with non-small molecule candidates | Poster Board #1033 (ACS-Fall 2026) - "We validated our methodology using established inhibitors and a suite of newly designed peptides targeting PRC2 components. Specifically, the IC50 value of the known inhibitor GSK126 obtained using this assay was consistent with values reported in existing literature, confirming the reliability and accuracy of our platform for characterizing hydrophobic and peptide-based inhibitors"

Genito-urinary Cancer • Hematological Malignancies • Lymphoma • Non Small Cell Lung Cancer • Ovarian Cancer • Prostate Cancer • Solid Tumor

Epigenetic and Non-Epigenetic Functions of EZH2 in Tumor Development: Structural Basis, Signaling Network, and Targeted Intervention Strategies. (PubMed, Curr Med Chem) - "Tazemetostat is the first FDA-approved EZH2 inhibitor for relapsed or refractory follicular lymphoma, while other agents such as EPZ-6438 and GSK126 show promising preclinical antitumor activity. This review summarizes the association between EZH2 and tumors, and the mechanisms and pharmacological properties of EZH2 inhibitors. Future research directions and challenges are also discussed to facilitate the development of EZH2-targeted anticancer therapies strategies."

Journal • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Oncology

ER-α36 protects renal tubular cells from high glucose–induced senescence and apoptosis via EZH2–PTEN epigenetic regulation of PI3K/AKT signaling (ERA 2026) - "Pathway dependency was tested using LY294002 (20 μM), and EZH2 involvement using GSK126 (500 nM). Image HG suppresses EZH2 and H3K27me3 at the PTEN promoter, increasing PTEN. ER-α36 overexpression restores EZH2/H3K27me3 and attenuates PTEN induction, whereas ER-α36 knockdown further decreases EZH2 (A–B); ChIP–qPCR confirms reduced H3K27me3 occupancy at the PTEN promoter (C–D)."

IO biomarker • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Nephrology • Renal Disease • ANXA5 • BCL2 • CASP3 • CASP7 • CDKN1A • ER • EZH2 • PTEN

EZH2 blockade reverses doxorubicin resistance by inducing metabolic vulnerability and enhancing DNA damage in breast cancer. (PubMed, Front Pharmacol) - "DOX-resistant breast cancer cell models were established and treated with the EZH2 inhibitors tazemetostat or GSK126, alone or in combination with DOX. EZH2 is a critical determinant of DOX resistance in breast cancer by sustaining DNA damage tolerance and metabolic homeostasis. Pharmacological targeting of EZH2 in combination with DOX represents a rational strategy to overcome chemoresistance in breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • EZH2

The Role of EZH2 ın Malıgnant Pleural Mesothelıoma and Beyond: Current Practıce and Future Perspectıves. (PubMed, Curr Oncol Rep) - "For nearly twenty years, platinum-pemetrexed chemotherapy has persisted as the unchanged standard treatment; although recent progress in immunotherapy has modestly disrupted this therapeutic plateau, survival outcomes remain disappointingly limited...Preclinical and early clinical data demonstrate that EZH2 inhibitors-including tazemetostat, valemetostat, GSK126, EPZ011989, tulmimetostat, and novel PROTAC-based degraders such as MS1943-can suppress tumor progression, modulate the tumor immune microenvironment, and restore therapeutic sensitivity...Further understanding the dual canonical and non-canonical roles of EZH2 in tumor biology will be key to optimizing targeted and combinatorial treatment strategies. Future research should focus on translating EZH2 inhibition into clinical benefit, identifying predictive biomarkers of response, and exploring rational combinations with chemotherapy, targeted drugs, or immunotherapy to improve survival outcomes in mesothelioma..."

IO biomarker • Journal • Review • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor • Targeted Protein Degradation • BAP1 • EZH2

EZH2 enhances PCV2 replication through inhibition of MMP1 and MMP12 transcription activity. (PubMed, Vet Res) - "Furthermore, we identified EZH2-regulated downstream genes by RNA sequencing (RNA-seq) and found that MMP1 and MMP12 were significantly upregulated when EZH2 methyltransferase activity was inhibited by GSK126...Conversely, upon depletion of the EZH2 methyltransferase domain, inhibition of MMP1 and MMP12 promoters is lifted, thereby enabling MMP1 and MMP12 to suppress PCV2 replication. Our findings establish a link between the histone methyltransferase EZH2 and the PCV2 life cycle, advance understanding of the mechanisms underlying PCV2 infection, and suggest that drugs targeting MMP1/MMP12 activity may provide potential therapeutic approaches to prevent and control PCV2 infection and spread."

Journal • Infectious Disease • EZH2 • MMP1

Epigenetic reprogramming of tissue-resident memory T cells in chronic inflammatory disorders and implications for targeted therapies. (PubMed, Epigenomics) - "Combined inhibition using the DNMT1-targeting degrader GSK-3484862 and the EZH2 inhibitor GSK126 reversed pathological programming, reducing cytokine production by >80% in ex vivo assays...This first epigenetic atlas of TRM cells in chronic inflammation reveals tissue-specific vulnerabilities, therapeutic targets (DNMT1, EZH2), and patient stratification biomarkers. Limitations include the ex vivo validation system and the need for larger multicentric biomarker validation studies."

Journal • Dermatology • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Arthritis • Inflammatory Bowel Disease • Psoriasis • Rheumatoid Arthritis • Rheumatology • CD69 • CD8 • DNMT1 • FOXP3 • IL17A • ITGAE • TET2

EZH2 inhibition via GSK-126 mitigates EndMT and atherosclerosis in diabetes: A translational epigenetic approach. (PubMed, Sci Adv) - "In human aortic endothelial cells exposed to high glucose/tumor necrosis factor-α or serum from patients with coronary artery disease, EZH2 blockade via GSK-126 or short hairpin RNA suppressed EndMT and reversed transcriptional programs assessed by RNA sequencing, including COL4A1 and NR2F2. These findings identify EZH2 as a driver of EndMT in diabetes-associated atherosclerosis and highlight EZH2 inhibition as a potential therapeutic strategy to limit vascular pathology."

Journal • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Diabetes • Metabolic Disorders • Oncology • APOE • COL4A1 • TNFA

EZH2 inhibition triggers a context-specific ACSS2-H3K9ac-HK2 metabolic circuit in EZH2 non-mutant solid tumors. (PubMed, Cell Oncol (Dordr)) - "We identified a novel ACSS2-H3K9ac-HK2 signaling axis that is characteristically activated in EZH2-non-mutant solid tumors and drives metabolic reprogramming and resistance to EZH2 inhibition."

Journal • Hematological Disorders • Hematological Malignancies • Melanoma • Oncology • Solid Tumor • ACLY • ACSS2 • EZH2

Dual Targeting of EZH2 and LSD1 Suppresses Hepatocellular Carcinoma via Disruption of Sonic Hedgehog Signaling. (PubMed, Int J Mol Sci) - "Functionally, dual pharmacological inhibition of EZH2 (GSK126) and LSD1 (SP2509) suppressed HCC cell proliferation, induced G1-phase arrest, and enhanced apoptosis, as evidenced by increased caspase-3/7 activity and decreased pro-caspase levels. Chromatin immunoprecipitation revealed reduced EZH2, LSD1, and STAT3 occupancy at the GLI1 promoter following dual inhibition, leading to the repression of GLI1 and its downstream targets. Collectively, these findings demonstrate that EZH2 and LSD1 cooperatively sustain GLI1-dependent SHH signaling in HCC, and that dual epigenetic inhibition represents a mechanistically defined therapeutic strategy."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • CASP3 • CASP7 • EZH2 • GLI1 • KDM1A • STAT3

KIF18B Promotes Neuroendocrine Prostate Cancer Progression through ITGB1-Mediated Dual Suppression of YAP1 (AUA 2026) - "Rescue experiments used EZH2 inhibitor GSK126 and Src inhibitor Saracatinib...KIF18B knockdown reduced xenograft tumor volume 61%; combined with cisplatin achieved 79% inhibition versus 35% cisplatin alone... We establish a SUMOylation-KIF18B-ITGB1-EZH2/Src-YAP1 axis driving NEPC through dual YAP1 suppression. KIF18B represents a promising biomarker and therapeutic target for precision NEPC treatment."

Genito-urinary Cancer • Genitourinary Neuroendocrine Carcinoma • Oncology • Prostate Cancer • Solid Tumor • ASCL1 • CHGA • EZH2 • ITGB1 • RB1 • SYP • TP53 • YAP1

A novel dual-target strategy against TNBC: Combining EZH2 inhibition and dopamine D1 receptor activation to restore immune balance (AACR 2026) - "We previously reported combining GSK126 (an EZH2 inhibitor) with A77636 (a dopamine D1 receptor [DRD1] agonist) produced superior antitumor effects compared to monotherapies...These findings uncover a distinctive therapeutic avenue that integrates epigenetic regulation with dopaminergic activation to restore immune responsiveness in TNBC. (This work was supported by DOD W81XWH2010065 to Eswar Shankar)."

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

Dual targeting GLI1 and EZH2 for treatment of invasive breast cancer (AACR 2026) - "The CompuSyn for drug synergy analysis, both the Combination Index (CI) and Dose Reduction Index (DRI) indicated that the combination therapy exhibited significant synergistic effects, where Vismodegib could reduce the dose by ~52-fold, while GSK126 could reduce the dose by ~22-fold. Form the findings, we believe that dual targeting GLI1-EZH2 has potential to become a novel and effective combination treatment for invasive breast cancer in the clinical setting."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CCND1 • EZH2 • GLI1 • MYC

Structure-guided dual targeting of EZH2 and dopamine D1 receptor suppresses TNBC growth and metastasis (AACR 2026) - "Computational modeling using a full-length AlphaFold EZH2 structure and three ligands (GSK126, A77636, SKF38393) identified canonical and cryptic binding pockets via PocketMiner and Fpocket, revealing the SET domain as the primary high-affinity site...Together, these silico-guided and experimental findings establish a translationally actionable dual-target strategy that synergistically inhibits TNBC growth and metastasis. (Supported by DOD: W81XWH2010065, Eswar Shankar.)."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CTCs • EZH2

HMGCS1 as a Potential Mediator of Resistance to EZH2 Inhibition via Ferroptosis mediated by PI3K/AKT/mTOR Pathway in the Pancreatic Neuroendocrine Neoplasms. (PubMed, Endocr Relat Cancer) - "Furthermore, combining GSK126 with everolimus, an mTOR inhibitor used clinically for pNENs, more effectively inhibited cell proliferation and tumor growth. In summary, Our findings reveal that the EZH2 inhibitor GSK126 induces ferroptosis by inhibiting the PI3K/AKT/mTOR pathway, suppressing pNENs progression, and HMGCS1 may mediate resistance to EZH2 inhibitors, offering new insights into pNENs treatment."

Journal • Endocrine Cancer • Hematological Disorders • Hematological Malignancies • Oncology • Pancreatic Cancer • Solid Tumor • EZH2 • HMGCS1

Mechanism of histone H3K27me3 demethylase therapy for restoring cisplatin sensitivity in refractory testicular cancer (AACR 2024) - "Importantly, we demonstrated that pharmacological inhibition of H3K27 methylation with the EZH2 inhibitor GSK-126 conferred cisplatin resistance to parental cells while induction of H3K27 methylation with the histone lysine demethylase inhibitor GSK-J4 resulted in a high degree of cisplatin sensitization of TGCT tumors including cisplatin resistant TGCT cells. 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."

Genito-urinary Cancer • Germ Cell Tumors • Oncology • Solid Tumor • Testicular Cancer

PRMT6-mediated EZH2 arginine methylation is critical for breast cancer development. (PubMed, Oncogenesis) - "Combination of PRMT6 inhibitor EPZ020411, and EZH2 inhibitor GSK126 effectively suppresses breast tumour growth in the mouse xenografts...Consistently, PRMT6 mediated EZH2 R509 methylation is also confirmed in PRMT6-knockout mice. Our findings reveal that PRMT6 inhibitors might be promising combination therapy for EZH2-targeting cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • EZH2