GSK2816126

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 patients.

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.

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.

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.

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.

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.

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.

Virtual screening and molecular dynamics simulations identified acetyldigitoxin (ADT) as a potent EZH2 inhibitor, demonstrating superior binding affinity (-10.90 kcal/mol) and complex stability compared to the known inhibitor GSK126...ADT induced G0/G1 cell cycle arrest and promoted apoptosis, accompanied by upregulation of pro-apoptotic genes (Bax, Caspase-3) and downregulation of anti-apoptotic (Bcl-2) and cell cycle (CyclinD1) genes. Our integrated findings position ADT as a repurposed drug candidate for targeting EZH2 in NSCLC, warranting further preclinical investigation including direct enzyme inhibition assays.

And intraperitoneal administrating the inhibitor of EZH2 with GSK126 significantly ameliorated the nephritis in MRL/lpr mice. This research reveals a novel epigenetic regulation of JAM-A by EZH2-DNMT3A cascade contributes to T cell adhesion capacity via the activation of Rap1a/β1-integrin in lupus patients.

Functional rescue assays were performed with KDM6B-specific siRNA and the H3K27me3 methyltransferase inhibitor GSK126...HOXB8 promotes inflammatory responses and metastatic potential in HGSOC cells by suppressing the KDM6B/C/EBPα signaling axis, inducing aberrant H3K27me3 modification, and upregulating CCND1. Targeting HOXB8-mediated pathways may provide novel therapeutic opportunities for limiting ovarian cancer progression.

EZH2 plays a crucial role in promoting malignant phenotypes in EC, and its expression level correlates with cellular sensitivity to EZH2 inhibitors. These findings suggest that EZH2 could serve as a valuable therapeutic target and predictive biomarker for personalized medicine in EC.

Rescue experiments using the EZH2 inhibitor GSK126 assessed the functional output of the OLFML2A-EZH2 axis via CCK-8, EdU assays...Comprehensive proteomic and molecular biology analyses further indicated that OLFML2A may play a role in cell cycle regulation through the modulation of EZH2. Our findings suggest that OLFML2A may facilitate cell cycle progression by regulating EZH2, implicating it as a potential therapeutic target for triple-negative breast cancer.