pemrametostat (GSK3326595) / Ipsen - LARVOL DELTA

Synergistic Efficacy of Dual Menin and PRMT5 Targeting Against NPM1 mutated and KMT2A-rearranged Leukemia (ASH 2024) - "First, we assessed the PRMT5-i JNJ-64619178 (JNJ) and GSK3326595 (GSK) as single drugs...There was significant drug synergy of both PRMT5-i with each of two novel Men-i VTP50469 (VTP) and KO-539, while we found only moderate growth inhibition and no synergy in HL60 cells (wildtype for KMT2A and NPM1) that served as negative control...Four weeks of in vivo treatment significantly reduced leukemia burden in peripheral blood and bone marrow and significantly enhanced mice survival compared to single drugs and vehicle control. The presented data underscore the therapeutic potential of combined Menin and PRMT5 inhibition as a novel synergistic approach to targeting NPM1mut and KMT2A-r leukemias and is already available for clinical investigation."

Clinical • Hematological Malignancies • Leukemia • Oncology • ANXA5 • ITGAM • JAK2 • KMT2A • MEIS1 • MEN1 • NPM1 • PBX3 • PRMT5

Protein Arginine Methyltransferase 5 Promotes Renal Fibrosis via Activation of the Epidermal Growth Factor Receptor Signaling Pathway (KIDNEY WEEK 2025) - "Methods Renal tubular deficient mice lacking PRMT5 and EPZ015938, a selective inhibitor of PRMT5, were utilized to investigate the role of PRMT5 in renal fibrosis across three murine models: unilateral ureteral obstruction (UUO), unilateral ischemia/reperfusion injury (UIRI), and 5/6 nephrectomy (SNx)...Notably, these interventions inhibited the phosphorylation of epidermal growth factor receptor (EGFR) as well as several intracellular signaling pathways implicated in the progression of renal fibrosis—specifically Smad3, ERK1/2, AKT, NF-kB, and STAT3. Conclusion These findings indicate that PRMT5 plays a critical role in the development of renal fibrosis through the activation of multiple profibrotic signaling pathways."

Cardiovascular • Fibrosis • Immunology • Reperfusion Injury • EGFR • PRMT5 • SMAD3 • STAT3

Protein Arginine Methyltransferase 5 Drives Pulmonary Arterial Remodeling in Pulmonary Arterial Hypertension (AHA 2025) - "However, the role of PRMT5 and its potential interplay with lactate in PAH remains unknown.Goal: To determine the role of PRMT5 in PA remodeling and PAH. Immunohistochemical, immunoblot, proteomic analyses, proliferation, apoptosis assays; SU5416/Hypoxia (SuHx) mouse and rat models of PH. PRMT5 was over-accumulated in SMα-actin-positive areas of small muscular PAs from PAH patients and rats with SuHx PH, and distal human PAH PASMCs compared to non-diseased controls, supporting increased protein SDMA modification, PASMC hyper-proliferation, and apoptosis resistance. Collectively, our data suggest that LDHA/lactate and PDGF-BB-driven PRMT5 up-regulation promotes PASMC hyper-proliferation, survival, PA remodeling, and PH via activating Akt/mTOR. Targeting PRMT5 signaling could represent potentially attractive strategy to treat PAH."

Cardiovascular • Pulmonary Arterial Hypertension • Respiratory Diseases • LDHA • PRMT5

PARP inhibitor and PRMT5 inhibitor synergy is independent of BRCA1/2 and MTAP status in breast cancer cells. (PubMed, Sci Rep) - "This study investigates the effects of two classes of PRMT5 inhibitors, GSK3326595 and TNG908, on breast cancer cell lines with different BRCA1/2 statuses to evaluate their therapeutic potential and synergy with PARP inhibitors. These findings highlight the potential of combining PRMT5 inhibitors with PARP inhibitors in a wide range of cancers beyond BRCA1/2 and MTAP mutants. Further investigation is warranted to elucidate the underlying mechanisms of sensitization and the timing of cellular responses to PRMT5 inhibition."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • BRCA2 • MTAP

PRMT1/PRMT5-Mediated Differential Arginine Methylation of CRIP1 Promotes the Recurrence of Small Cell Lung Cancer after Chemotherapy. (PubMed, Int J Biol Sci) - "Notably, combination therapy using PRMT5 inhibitor GSK3326595 along with cisplatin and etoposide significantly delayed the recurrence of SCLC. Our findings reveal the promoting effect of post-chemotherapy inflammation on tumor recurrence from an epigenetic perspective and provide a potential therapeutic strategy for SCLC treatment."

Journal • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Targeted Protein Degradation • CRIP1 • PRMT1

Phase 1b and Dose-Expansion Study of GSK3326595, a PRMT5 Inhibitor as Monotherapy and in Combination With Pembrolizumab in Patients With Advanced Cancers. (PubMed, Ann Oncol) - P1 | "GSK3326595 monotherapy demonstrated modest antitumor activity. Further research in ACC and NHL is warranted."

Journal • Monotherapy • P1 data • Adenoid Cystic Carcinoma • B Cell Lymphoma • Breast Cancer • Diffuse Large B Cell Lymphoma • Fatigue • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Therapeutic targeting of protein arginine methyltransferases reduces breast cancer progression by disrupting angiogenic pathways. (PubMed, Biochem Biophys Rep) - "Several small-molecule PRMT inhibitors, including GSK3326595 and EPZ015666, have entered early-phase clinical trials for solid tumors. This review examines the mechanistic basis and therapeutic rationale for targeting PRMTs in breast cancer and discusses combination approaches to overcome resistance. We integrate preclinical and emerging clinical data to highlight the potential antiangiogenic and tumor-suppressive effects of PRMT inhibitors, providing insights for future therapeutic strategies for breast cancer."

Journal • Review • Breast Cancer • Oncology • Solid Tumor • HIF1A • PRMT1

TARGETING ARGININE METHYLTRANSFERASE PRMT5 AS A PROMISING THERAPEUTIC STRATEGY IN NKTCL (ICML 2025) - "Druggability was evaluated in NKTCL cell lines and mouse models using PRMT5 inhibitors GSK3326595 and AMG193. Overall, this study is the first to demonstrate PRMT5 overexpression in NKTCL and its vulnerability to targeted therapy. Both monotherapy with PRMT5 inhibitors and combination treatments show significant antitumor effects, providing new insights for the further treatment of this disease."

IO biomarker • Lymphoma • Natural Killer/T-cell Lymphoma • CD4 • CDKN2A • MTAP • PRMT5

TARGETING MAT2A ALTERS THE METHYLATION LANDSCAPE AND DNA DAMAGE RESPONSE IN MULTIPLE MYELOMA, REVEALING NOVEL COMBINATION STRATEGIES. (EHA 2025) - "Moreover, FIDAS-5 was able to improve bortezomib-based treatment...The impact of MAT2A depletion on DNA methylation and histone methylation was evaluated using Enzymatic Methyl sequencing (EM-seq) and western blot, while the impact on the transcriptome was determined by RNA sequencing (RNA-seq).Doxycycline inducible stable KD of MAT2A in MM cells using shRNA confirmed the tumor promoting role of MAT2A... In conclusion, our research highlights that targeting MAT2A in MM cells reverts aberrant methylation processes and impairs several pro-tumoral signalling pathways, offering promising avenues for developing more effective combination treatments for MM."

Hematological Malignancies • Multiple Myeloma • Oncology • ANXA5 • MAT2A

TARGETING ARGININE METHYLTRANSFERASE PRMT5 AS A PROMISING THERAPEUTIC STRATEGY IN NKTCL (EHA 2025) - "Druggability was evaluated in NKTCL cell lines and mouse models using PRMT5 inhibitors GSK3326595 and AMG193. Overall, this study is the first to demonstrate PRMT5 overexpression in NKTCL and its vulnerability to targeted therapy. Both monotherapy with PRMT5 inhibitors and combination treatments show significant antitumor effects, providing new insights for the further treatment of this disease."

IO biomarker • Epstein-Barr Virus Infections • Hematological Malignancies • Lymphoma • Natural Killer/T-cell Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • CD4 • CDKN2A • MTAP • PRMT5

PRMT5 Regulates Senescence in Retinal Ganglion Cells by Targeting the Wnt/β-Catenin Signaling Cascade. (PubMed, Invest Ophthalmol Vis Sci) - "Additionally, the role of the protein arginine methyltransferase 5 (PRMT5)-regulated Wnt/β-catenin pathway in RGC senescence was investigated via intravitreal injection of GSK3326595 and CHIR99021 in mice...Taken together, these findings highlight the critical role of the PRMT5-regulated Wnt/β-catenin pathway in RGC senescence and neurodegeneration. Targeting this pathway represents a promising therapeutic strategy for glaucoma."

Journal • Cardiovascular • CNS Disorders • Glaucoma • Ophthalmology • PRMT5

PRMT5 Regulates Pulmonary Vascular Smooth Muscle Cell Proliferation and Survival in Pulmonary Arterial Hypertension (ATS 2025) - "Furthermore, pharmacological inhibition of PRMT5 with GSK3326595 inhibited human PAH PASMCs proliferation in a concentration-dependent manner. PRMT5 is up-regulated in PASMCs in human PAH lungs in LDHA/lactate-dependent manner, leading to increased cell proliferation and survival. Further studies are needed to evaluate the therapeutic potential of PRMT5 inhibition as a novel strategy to treat PAH."

IO biomarker • Cardiovascular • Oncology • Pulmonary Arterial Hypertension • Respiratory Diseases • BCL2L11 • LDHA • PRMT5

Targeting PRMT5 to enhance T cell-mediated antitumor immune responses. (IMMUNOLOGY 2025) - "Our data show that GSK3326595 significantly suppresses PRMT5 activity in tumors and T cells regardless of MTAP status. Mechanistically, transcriptomic and proteomic profiling analysis reveals that MRTX1719 successfully reduces activation of the PI3K pathway, a well-documented immune-resistant pathway. Furthermore, the combination of MRTX1719 in combination with immune checkpoint blockade (ICB) leads to superior antitumor activity in two syngeneic murine models with MTAP-loss tumor, providing a strong rationale for the clinical development of PRMT5i-based IO combinations.Keywords: Animals Human Rodent; Cells T Cells; Techniques/Approaches Molecular Biology"

Oncology • MTAP

PRMT5 Inhibitor Synergizes with Chemotherapy to Induce Resembling Mismatch Repair Deficiency and Enhance Anti-TIGIT Therapy in Microsatellite-Stable Colorectal Cancer. (PubMed, Adv Sci (Weinh)) - "Importantly, combining the epigenetic anti-tumor drug GSK3326595 with CPT-11 significantly upregulates the immune receptor tyrosine-based inhibitory motif (TIGIT) level on CD8+ T cells and subsequently demonstrates impressive anti-tumor efficacy in vivo when additional anti-TIGIT is included. Collectively, this study reveals the crucial role of PRMT5 blockade combined with CPT-11 in inducing a mismatch repair deficiency-like state and provides a novel triple-drug combination therapy strategy as a potential treatment for patients with MSS CRC."

Journal • Mismatch repair • Colorectal Cancer • Gene Therapies • Oncology • Solid Tumor • CD8 • CGAS • PMS2 • STING • TIGIT

Preclinical evaluation of drugs for the treatment of MTAP-deficient cancers [WITHDRAWN] (AACR 2025) - "Subsequently, with in vitro viability assay we showed that the two PRMT5 inhibitors, GSK3326595 and MRTX1719 exhibited strong anti-proliferative effects against MTAP-deficient cells. This selective PRMT5 inhibitor developed a superior anti-tumor effect, achieving a tumor growth inhibition of over 100% after three weeks of treatment. In summary, our findings may advance the development of novel therapeutic strategies for MTAP-deficient cancers."

Preclinical • Bladder Cancer • Brain Cancer • CNS Tumor • Genito-urinary Cancer • Glioblastoma • Oncology • Pancreatic Cancer • Solid Tumor • MAT2A • MTAP • PRMT5

Developing PRMT5 inhibition-based Immuno-oncology combination therapies in MTAP-loss tumors (AACR 2025) - "Two PRMT5 inhibitors, GSK3326595 (substrate-competitive) and MRTX1719 (MTA-cooperative), were evaluated on tumor and immune cells. The combination also increased CD8+ T cell proliferation in MTAP-KO tumor tissues. Collectively, our results provide a strong rationale for the clinical development of MRTX1719-based IO combinations in MTAP-loss tumors."

Combination therapy • Immuno-oncology • Oncology • CD8 • MTAP

Alternative Splicing: A Key Regulator in T cell Response and Cancer Immunotherapy. (PubMed, Pharmacol Res) - "AS modulators such as PRMT5 inhibitor GSK3326595 enhance immunotherapy efficacy by upregulating MHC class II expression and promoting T cell infiltration, while RBM39 inhibitor indisulam induces tumor-specific neoantigens. Future efforts should focus on refining AS-targeting therapies, identifying predictive biomarkers, and integrating these approaches into clinical applications. This review highlights the therapeutic potential of AS modulation in cancer immunotherapy and its implications for advancing precision oncology."

IO biomarker • Journal • Review • Immune Modulation • Immunology • Oncology • CD8 • RBM39

PRMT5-Mediated ALKBH5 Methylation Promotes Colorectal Cancer Immune Evasion via Increasing CD276 Expression. (PubMed, Research (Wash D C)) - "Finally, we demonstrated that combining an anti-PD1 antibody with the PRMT5 inhibitor GSK3326595 markedly halts the progression of CRC. Our findings could serve as a basis for the development of a PRMT5-meR316-ALKBH5-CD276 axis-targeting treatment approach for CRC."

IO biomarker • Journal • Colorectal Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ALKBH5 • CD276 • TRIM28

ORIGANOID MODELS FOR PREDICTING DRUG RESPONSE IN HIGH GRADE SEROUS OVARIAN CANCER (IGCS 2024) - "Drug screening for organoids: Grown organoids were dissociated and re-seeded on the 384-well plated; 23 drug treatment regimens were selected including carboplatin,oxaliplatin,doxorubicin hydrochloride, olaparib, niraparib, fluzoparib, gemcitabine hydrochloride, topotecan, paclitaxel, docetaxel, Adriamycin liposome, Etoposide, Wee1 inhibitor (adavosertib), CDK4/6 inhibitor(palbociclib ), BYL-719(PI3Kα inhibitor), 5-Fluorouracil, Irinotecan, Cyclophosphamide hydrate, Vorinostat (HDACi), Ruxolitinib(JAK1/2 inhibitor), Mirvetuximab, Pemrametostat (PRMT5 inhibitor). Clinical applications of PDOs for personalized monitoring of tumor reoccurrence and in vitro drug sensitivity profiling. Palbociclib may be a better treatment option for PARPi-resistant recurrent patients."

High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • PIK3CA

MTA-cooperative PRMT5 inhibitors enhance T cell-mediated antitumor activity in MTAP-loss tumors. (PubMed, J Immunother Cancer) - "Collectively, our results provide a strong rationale and mechanistic insights for the clinical development of MRTX1719-based IO combinations in MTAP-loss tumors."

Journal • Oncology • MTAP

MTA-cooperative PRMT5 inhibitors enhance T cell-mediated antitumor activity in MTAP-loss tumors (J Immunother Cancer) - "GSK3326595 significantly suppresses PRMT5 activity in tumors and T cells regardless of the MTAP status. However, MRTX1719, a methylthioadenosine-cooperative PRMT5 inhibitor, exhibits tumor-specific PRMT5 inhibition in MTAP-loss tumors with limited immunosuppressive effects....In addition, MRTX1719 sensitizes MTAP-loss tumor cells to the killing of tumor-reactive T cells. Combining MRTX1719 and anti-PD-1 leads to superior antitumor activity in mice bearing MTAP-loss tumors."

Preclinical • Oncology

Phase I/II study of the clinical activity and safety of GSK3326595 in patients with myeloid neoplasms. (PubMed, Ther Adv Hematol) - P1/2 | "The safety profile was broadly consistent with other published PRMT5 inhibitor studies. ClinicalTrials.gov: NCT03614728."

Journal • P1/2 data • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Fatigue • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • SRSF2 • U2AF1

PRMT5 inhibitor synergizes with PARP inhibitors in triple-negative breast cancer cells (AACR 2024) - "In this study, we evaluated the pre-clinical benefit of combining PARP inhibitors with a PRMT5 inhibitor in TNBC cells. Human TNBC cell lines with wildtype BRCA1 (MDA-MB-468, HCC1806) and mutant BRCA1 (MDA-MB-436, SUM149-PT) were treated with varying doses of two PARP inhibitors (Olaparib, Talazoparib) and a PRMT5 inhibitor (GSK3326595) as single agents or in combination. We report that PRMT5 inhibition synergizes with both Olaparib and Talazoparib, to potentiate cell death in two BRCA1WT but not in BRCA1mut TNBC cell lines. Furthermore, we show that inhibiting PRMT5 in BRCA1WT cells upregulates the mRNA expression of RAD50, a DNA damage sensing gene in the HR pathway. Our ongoing study is to delineate the molecular mechanism of action for the observed synergy and whether PRMT5 inhibition can overcome resistance to PARP inhibitors."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • PRMT5 • RAD50

Combination of MTA-cooperative PRMT5 inhibitor and direct mutant-selective KRAS inhibitors as a novel therapeutic approach for MTAP-deficient pancreatic cancer (AACR 2024) - "We found that suppression of PRMT5 activity using two distinct first-generation clinical candidate small molecule inhibitors (JNJ-64619178 and GSK3326595) demonstrated single agent activity and reduced PDAC cell growth...In support of our hypothesis, we demonstrated that combination treatment with MRTX1719 and mutant selective KRAS inhibitors (G12Ci/MRTX849 and G12Di/MRTX1133) further sensitized KRASG12C/D-mutant PDAC cells to KRAS inhibition in short- and long-term growth assays as well as in vivo xenograft studies. Our ongoing studies are evaluating the consequences of co-targeting PRMT5 and KRAS on gene expression changes using RNA-Seq and cancer cell signaling pathways using RPPA analyses. In summary, our data support concurrent inhibition of PRMT5 and KRAS as a promising therapeutic strategy for MTAP-deficient KRAS-mutant pancreatic cancer."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • MTAP

Genome-wide drug anchor screens identify CAAP1 and AKAP17A as regulators of PRMT5 inhibitor sensitivity (AACR 2024) - "CAAP1 or AKAP17A knockout in MTAP-deleted cancer cell lines sensitized the cells to PRMT5 inhibitors including the clinical stage MTA-cooperative inhibitors, TNG908 and TNG462, and the non-MTA-cooperative inhibitor, GSK3326595. S. Yoda and M. R. Tonini contributed equally."

Oncology • CDKN2A • MTAP