GSK591 / GSK, Ipsen - LARVOL DELTA

The Arginine Methyltransferase PRMT5 Regulates Maintenance and TKI Resistance of Self-Renewing FLT3-ITD AML LSC (ASH 2024) - "We confirmed dose and time-dependent inhibition of FLT3-ITD AML cells by the PRMT5 inhibitors (PRMT5i), GSK-591 and LLY-283, and showed that combination of PRMT5i with FLT3 TKI (Quizartinib, Giltertinib) synergistically inhibited FLT3-ITD AML cells. We conclude that PRMT5 plays a critical role in maintenance of self-renewing FLT3-ITD AML LSC and in their persistence following TKI treatment, and that combined PRMT5i and TKI treatment effectively depletes FLT3-ITD AML LSC with disease regenerating capacity. We identify mechanisms underlying the synergistic effects of the combination of PRMT5i with TKI, including depletion of FLT3-ITD protein, activation of the p53 pathway, enhanced inhibition of STAT5, MAPK and AKT signaling, and increased alternative splicing events affecting key LSC maintenance pathways."

Clinical • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CD34 • FLT3 • MDM4 • PRMT5 • STAT5 • TET2

ATP6V0A4 as a novel prognostic biomarker and potential therapeutic target in oral squamous cell carcinoma. (PubMed, BMC Oral Health) - "ATP6V0A4 may serve as a novel prognostic biomarker and potential therapeutic target in oral squamous cell carcinoma."

Biomarker • IO biomarker • Journal • Oncology • Oral Cancer • Squamous Cell Carcinoma • ATP6V0A4

Overcoming Taxane Resistance Through PRMT5 Inhibition: Targeting Epigenetic Mechanisms (EACR 2025) - "CRPC treatment primarily relies on chemotherapy, particularly taxanes such as docetaxel (Dtx) and cabazitaxel (Cbz)...PRMT5 inhibition was assessed for its role in overcoming taxane resistance using pharmacological inhibitors (CMP5, GSK591, HLCL61) and shRNA knockdown, followed by functional assays including cell viability, clonogenic assay, apoptosis (Annexin V / Caspase-3/7 assays) and cell cycle analysis... Pharmacological inhibition of PRMT5 modulates cell cycle and transcriptional pathways, re-sensitizing resistant cells to taxane-based chemotherapy, with RNA-ChIP integration revealing key mechanisms related to cell cycle regulation. Given that PRMT5 inhibitors are already being evaluated in clinical trials, our findings further support its potential as a therapeutic target for taxane-refractory patients."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ABL1 • ANXA5 • CASP3 • CASP7 • CCND1 • MYC • PRMT5 • RB1

The mechanism of PRMT5 in causing smoking-induced lung cancer and development of EGFR Tyrosine kinase inhibitor resistance (AACR 2025) - "In NSCLC, EGFR-TKI treatments with Osimertinib initially reduce tumor growth but often lead to resistance in about 19 months...Also, using qPCR the effects of PRMT5i after CSE treatment were studied on inflammatory cytokines.The efficacy of PRMT5i (GSK591) on PC9OR cells were studied using bioprinted with GelMA with a R-Gen 200 bioprinter.After 24 and 48 hours of CSE treatment PRMT5 gene expression was increased as observed using qPCR in TKI-resistant H3255P/OR (1.5-11 fold) and PC9/OR (1.5-17 fold) (p<0.05) cells respectively...Preliminary results with PC9OR along with HLF (Human lung fibroblasts) bioprinted spheroids showed 40% inhibition of spheroid count/microscopic field by a combination of PRMT5i and OR compared to OR alone.In conclusion, we infer that PRMT5 is overexpressed in TKI-resistant cells, leading to increased oncogenic potential. Modulating PRMT5 levels could enhance the effectiveness of EGFR TKIs in NSCLC patients."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CXCL8 • EGFR • IL1B • PRMT5 • TNFA

Decoding mitochondrial stress genes in DCM: towards precision diagnosis and therapy. (PubMed, Hereditas) - "This research highlights key genes associated with mitochondrial oxidative stress-VCL, ABCB1, JAK2, KDR, NGF-that show differential expression in DCM and myocardial infarction. These findings underscore their diagnostic potential and pave the way for new therapeutic strategies."

Journal • Cardiomyopathy • Cardiovascular • Myocardial Infarction • ABCB1 • JAK2 • KDR • NGF

Tumor-intrinsic PRMT5 upregulates FGL1 via methylating TCF12 to inhibit CD8+ T-cell-mediated antitumor immunity in liver cancer. (PubMed, Acta Pharm Sin B) - "Mechanistically, PRMT5 catalyzed symmetric dimethylation of transcription factor 12 (TCF12) at arginine 554 (R554), prompting the binding of TCF12 to FGL1 promoter region, which transcriptionally activated FGL1 in tumor cells. Notably, combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice. Collectively, our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy."

IO biomarker • Journal • Hepatology • Liver Cancer • Oncology • Solid Tumor • CD8 • FGL1 • PRMT5 • TCF12

Spliceosomal vulnerability of MYCN-amplified neuroblastoma is contingent on PRMT5-mediated regulation of epitranscriptomic and metabolomic pathways. (PubMed, Cancer Lett) - "Here we evaluate the highly selective first-in-class PRMT5 inhibitor GSK3203591 and its in vivo analogue GSK3326593 as targeted therapeutics for MNA neuroblastoma...In vivo efficacy of GSK3326593 is confirmed by increased survival of Th-MYCN mice, with drug treatment triggering splicing events and protein decreases consistent with in vitro data. Together our study demonstrates the PRMT5-dependent spliceosomal vulnerability of MNA neuroblastoma and identifies the epitranscriptome and glutamine metabolism as critical determinants of this sensitivity."

Journal • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • METTL3 • MYCN • YTHDF3

Machine learning-based integration develops a multiple programmed cell death signature for predicting the clinical outcome and drug sensitivity in colorectal cancer. (PubMed, Anticancer Drugs) - "In addition, the high-MPCDI group was more sensitive to AZD1332, Foretinib, and IGF1R_3801, and insensitive to AZD3759, AZD5438, AZD6482, Erlotinib, GSK591, IAP_5620, and Picolinici-acid, which suggests that the MPCDI can guide drug selection for CRC patients. As a new clinical classifier, the MPCDI can more accurately distinguish CRC patients who benefit from immunotherapy and develop personalized treatment strategies for CRC patients."

Clinical data • Journal • Machine learning • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Targeting Epigenetic and Post-translational Modifications Regulating Pyroptosis for the Treatment of Inflammatory Diseases. (PubMed, Pharmacol Res) - "We also illustrate these within pyroptosis-associated inflammatory diseases. In addition, we discuss the effects of novel therapeutic strategies targeting epigenetic and post-translational modifications on pyroptosis, and provide prospective insight into the regulation of pyroptosis for the treatment of inflammatory diseases."

Journal • Review • CNS Disorders • Diabetes • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • Metabolic Disorders • Oncology • Rheumatology • Targeted Protein Degradation

Establishing the role of PRMT5 in lung cancer tumorigenicity and modulation of expression in smokers (AACR 2024) - "We also compared the expression of these biomarkers in erlotinib resistant (ER) and Osimertinib resistant (OR) cells using Western blotting. PRMT5 was inhibited using GSK591 (PRMT5i) to evaluate its sensitivity to EGFR TKIs (ER and OR)...Modulation of PRMT5 can prove to be groundbreaking and revolutionary, as it may increase the efficacy of EGFR TKIs.[S.N.A. and M.P. contributed equally to this work.]"

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CXCL8 • IL1B • PRMT5 • TNFA

PRMT5 inhibition shows in vitro efficacy against H3K27M-altered diffuse midline glioma, but does not extend survival in vivo. (PubMed, Sci Rep) - "Two of the most effective inhibitors, LLY-283 and GSK591, were targeted against PRMT5 using distinct binding mechanisms and reduced the viability of a subset of DMG cells expressing wild-type TP53 and mutant ACVR1. RNA-sequencing and phenotypic analyses revealed that LLY-283 could reduce the viability, clonogenicity and invasion of DMG cells in vitro, representing three clinically important phenotypes, but failed to prolong survival in an orthotopic xenograft model. Together, these data show the challenges of DMG treatment and highlight PRMT5 inhibitors for consideration in future studies of combination treatments."

Journal • Preclinical • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • ACVR1 • PRMT5 • TP53

CircMMP2(6,7) cooperates with β-catenin and PRMT5 to disrupt bone homeostasis and promote breast cancer bone metastasis. (PubMed, Cancer Res) - "Treatment with GSK591, a selective PRMT5 inhibitor, effectively inhibited circMMP2(6,7)/β-catenin/PRMT5 complex-induced breast cancer bone metastasis. These findings reveal a role for circMMP2(6,7) in bone homeostasis disruption and shed light on the mechanisms driving breast cancer bone metastasis."

Journal • Breast Cancer • Oncology • Solid Tumor • CTNNB1 • LGALS3 • S100A4

(S)-2-(Cyclobutylamino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)isonicotinamide Attenuates RANKL-Induced Osteoclast Differentiation by Inhibiting NF-κB Nuclear Translocation. (PubMed, Int J Mol Sci) - "EPZ015866 attenuated RANKL-induced osteoclast differentiation, and its inhibitory effect was more significant than EPZ015666. Both EPZ compounds inhibited the nuclear translocation of NF-κB by inhibiting the dimethylation of the p65 subunit, which eventually prevented osteoclast differentiation and bone resorption. Hence, EPZ015866 may be a potential drug candidate for the treatment of osteoporosis."

Journal • Osteoporosis • Rheumatology • CTSK • NFATC1 • NF-κβ • PRMT5 • RELA

PRMT5 Inhibition Enhances Elimination of FLT3-ITD AML Stem Cells in Combination with TKI Treatment (ASH 2022) - "The combination of GSK-591 or LLY-283 with either of the FLT3 TKIs Quizartinib or Giltertinib resulted in synergistically enhanced inhibition of FLT3-ITD+ MOLM-13 and MV4-11 AML cells, compared to TKI or PRMT5 inhibitor alone. An epigenetic probe screen identified PRMT5 as a key regulator of FLT3-ITD AML cell viability. We show an important role for PRMT5 in maintenance of murine and human FLT3-ITD AML stem cells and in their persistence following FLT3 TKI treatment. Treatment with a PRMT5 inhibitor in combination with a FLT3 TKI could be a promising approach to enhance elimination of FLT3-ITD AML stem cells."

Combination therapy • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • CD34 • CD38 • FLT3 • GLI2 • PRMT1 • PRMT5 • PRMT7 • TET2

TP53 mutations and RNA-binding protein MUSASHI-2 drive resistance to PRMT5-targeted therapy in B-cell lymphoma. (PubMed, Nat Commun) - "We identify TP53 and RNA-binding protein MUSASHI2 (MSI2) as the top-ranked sensitizer and driver of resistance to specific PRMT5i, GSK-591, respectively. BCL-2 depletion or inhibition with venetoclax synergizes with a PRMT5 inhibitor by inducing reduced cell growth and apoptosis. Thus, we propose a therapeutic strategy in lymphoma that combines PRMT5 with MSI2 or BCL-2 inhibition."

IO biomarker • Journal • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • MSI2 • MYC • PRMT5 • TP53

PRMT5 Inhibition Promotes PD-L1 Expression and Immuno-Resistance in Lung Cancer. (PubMed, Front Immunol) - "The combination of PRMT5 inhibition and ani-PD-L1 therapy resulted in an increase in the number and enhanced the function of tumor-infiltrating T cells. Our findings address an unmet clinical need in which combining PRMT5 inhibition with anti-PD-L1 therapy could be a promising strategy for lung cancer treatment."

IO biomarker • Journal • Lung Cancer • Oncology • Solid Tumor • CD8 • PRMT5

TP53 Mutations and RNA Binding Protein Musashi 2 Drive Resistance to PRMT5-Targeted Therapy in B-Cell Lymphoma (ASH 2021) - "Interestingly, in the human B cell line P493-6 that express a conditional, tetracycline-regulated c-MYC, the depletion of c-MYC significantly increased the anti-proliferative activity of GSK-591 and Ro alone or in combination. We demonstrated that TP53 LOF and MSI2 expression could be used as biomarkers for patient stratification. Moreover, we proposed two novel drug combination strategies, with venetoclax or a MSI2 inhibitor, to be considered in further clinical studies with PRMT5 inhibitors."

IO biomarker • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • LY9 • MSI2 • MYC • PRMT5 • TP53

[VIRTUAL] PRMT5 inhibition reduces viability and stemness of pediatric high grade glioma (AACR 2021) - "The 2 most effective compounds inhibit PRMT5 (GSK591 and LLY-283) reducing viability >50% in adherent and spheroid screens. However a reduction in stemness, as seen in vitro¸ does not always reduce primary tumor burden. Therefore proteomic characterization of neural differentiation in the primary PDX samples is underway, and investigation into secondary tumor initiation would be warranted.Our data shows PRMT5 inhibitors are a promising new target for DIPG, specifically in ACVR1 mutant DIPG, and justifies further in vivo investigations into changes in tumor initiation capacity and exploration of rational combinations to improve survival outcome."

Clinical • Diffuse Intrinsic Pontine Glioma • Glioblastoma • Glioma • Oncology • Solid Tumor • ACVR1 • APOE • DKK1 • PRMT5

PRMT5 Promotes EMT Through Regulating Akt Activity in Human Lung Cancer. (PubMed, Cell Transplant) - "Further study reveals that silencing PRMT5 by lentivirus-mediated shRNA or blocking of PRMT5 by specific inhibitor GSK591 attenuates the expression levels of EMT-related markers in vivo, using the xenograft mouse model...Altogether, our results demonstrate that PRMT5 serves as a critical oncogenic regulator and promotes EMT in human lung cancer cells. More importantly, our findings also suggest that PRMT5 may be a potential therapeutic candidate for the treatment of human lung cancer."

Journal • Lung Cancer • Oncology • Solid Tumor • PRMT5

PRMT5 functionally associates with EZH2 to promote colorectal cancer progression through epigenetically repressing CDKN2B expression. (PubMed, Theranostics) - "Importantly, we found that the combined interventions exerted a synergistic inhibitory effect of combined treatment with PRMT5i (GSK591) and EZH2i (GSK126) on the growth of CRC cells/xenografts in vitro and in vivo. PRMT5 functionally associates with EZH2 to promote CRC progression through epigenetically repressing CDKN2B expression. Thus, our findings raise the possibility that combinational intervention of PRMT5 and EZH2 may be a promising strategy for CRC therapy."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CDKN2B • EZH2 • PRMT5

PRMT5 inhibition disrupts splicing and stemness in glioblastoma. (PubMed, Nat Commun) - "Using two orthogonal-acting inhibitors of PRMT5 (GSK591 or LLY-283), we show that pharmacological inhibition of PRMT5 suppresses the growth of a cohort of 46 patient-derived GBM stem cell cultures, with the proneural subtype showing greater sensitivity. Importantly, we demonstrate that LLY-283 is brain-penetrant and significantly prolongs the survival of mice with orthotopic patient-derived xenografts. Collectively, our findings provide a rationale for the clinical development of brain penetrant PRMT5 inhibitors as treatment for GBM."

Journal • Glioblastoma • Oncology • Solid Tumor • PRMT5

PRMT5 regulates colorectal cancer cell growth and EMT via EGFR/Akt/GSK3β signaling cascades. (PubMed, Aging (Albany NY)) - "Using PRMT5 stable depletion cell lines and specific inhibitor, we discover that down-regulation of PRMT5 by shRNA or inhibition of PRMT5 activity by specific inhibitor GSK591 markedly suppresses CRC cell proliferation and cell cycle progression, which is closely associated with PRMT5 enzyme activity...Collectively, our results reveal that PRMT5 promotes CRC cell proliferation, cell cycle progression, and EMT via regulation of EGFR/Akt/GSK3β signaling cascades. Most importantly, our findings also suggest that PRMT5 may be a potential therapeutic target for the treatment of human colorectal cancer."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • PRMT5 • PTEN

PRMT5 Promotes Human Lung Cancer Cell Apoptosis via Akt/Gsk3β Signaling Induced by Resveratrol. (PubMed, Cell Transplant) - "Our results indicated that inhibition or down-regulation of PRMT5 by GSK591, a PRMT5-specific inhibitor, or shRNAs markedly enhanced cell apoptosis and chemosensitivity stimulated by resveratrol. Further investigation showed that inhibition or down-regulation of PRMT5 further reduced Akt/GSK3β phosphorylation and the downstream targets cyclin D1 and E1 expression upon resveratrol treatment. Our findings suggest that PRMT5 is a pivotal mediator for human lung cancer cell death induced by resveratrol, which also reveals that PRMT5 may serve as a new therapeutic target for the treatment of human lung cancer."

Journal • Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

Targeting PRMT5/Akt signalling axis prevents human lung cancer cell growth. (PubMed, J Cell Mol Med) - "We found that the down-regulation of PRMT5 by shRNA or the inhibition of PRMT5 by specific inhibitor GSK591 dramatically suppressed cyclin E1 and cyclin D1 expression and cell proliferation...Altogether, our results indicate that PRMT5 promotes human lung cancer cell proliferation through direct interaction with Akt and regulation of Akt activity. Our findings also suggest that targeting PRMT5 may have therapeutic potential for treatment of human lung cancer."

Journal • Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

EFFECT OF THE PROTEIN ARGININE METHYLTRANSFERASE PRMT5 INHIBITION IN GLIOMA STEM-LIKE CELLS (SNO 2018) - "...By using a panel of molecularly distinct glioma stem like cells (GSCs) we investigated the effect of PRMT5 inhibitor GSK591 on cell viability...Tight regulation of Akt-mTOR pathway enables cancer cells to survive in harsh conditions via activation of autophagy signaling. Currently, we are investigating the role of PRMT5 in tumor growth through the concomitant regulation of autophagy signaling in GSCs."

Brain Cancer • Oncology • Solid Tumor