pemrametostat (GSK3326595) / Ipsen - LARVOL DELTA

Resetting the Aberrant Methylation Landscape and DNA Damage Response in Multiple Myeloma Through MAT2A Targeting Reveals Novel Combination Strategies. (IMS 2026) - " MAT2A knockdown (KD) in OPM2 and AMO-1 cell lines was achieved using doxycycline inducible lentiviral shRNA vectors targeting MAT2A. In conclusion, targeting MAT2A in MM cells reverts aberrant methylation and impairs pro-tumoral signalling offering promising avenues for more effective combination therapies."

Hematological Malignancies • Multiple Myeloma • ANXA5 • KRAS • MAT2A

Design and synthesis of the first PARP1 and PRMT5 dual inhibitors for the treatment of breast cancer. (PubMed, Eur J Med Chem) - "Notably, in the BRCA wild-type MDA-MB-231 xenograft tumor model, compound 8I exhibited more potent in vivo antitumor activity than single-agent treatment with the PARP1 inhibitor Olaparib or the PRMT5 inhibitor GSK3326595, and displayed efficacy comparable to the combination of the two agents. In conclusion, this study established a new class of PARP1/PRMT5 dual inhibitors with prominent synergistic antitumor effects, which hold potential for the treatment of breast cancer."

Journal • Breast Cancer • Gene Therapies • Oncology • Solid Tumor • BRCA • BRCA1 • BRCA2 • RAD51

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

Flavokawain A inhibits high glucose-induced malignant progression of lung cancer cells by suppressing PRMT5-mediated PTEN neddylation and nuclear translocation. (PubMed, Oncol Lett) - "Cellular NEDD8 levels were manipulated by overexpressing Flag-NEDD8 and using MLN4924, an inhibitor of NEDD8-activating enzyme. Notably, GSK3326595 exhibited an inhibitory effect similar to that of FKA. The results indicated that FKA suppressed high glucose-induced carcinogenic effects by inhibiting PRMT5-mediated PTEN neddylation and subsequent nuclear translocation."

Journal • Diabetes • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • NEDD8 • PRMT5 • PTEN

PRMT5-mediated methylation of LKB1 controls PD-L1 expression in NSCLC. (PubMed, Biomed J) - "These findings identify a PRMT5-LKB1-AMPK regulatory axis controlling PD-L1 expression in a cell-context-dependent manner and suggest that LKB1 status may serve as a predictive biomarker for combining PRMT5 inhibitors with ICB in NSCLC. This strategy offers a potential therapeutic avenue to overcome immunotherapy resistance in LKB1-proficient NSCLC."

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD4 • CD8 • PD-L1 • PRMT5 • STK11

Emerging role of protein arginine methyltransferase 5 in gastrointestinal cancer (Review). (PubMed, Oncol Lett) - "However, PRMT5 inhibitors (e.g., GSK3326595 and JNJ-64619178) demonstrate antitumor effects in preclinical models and methylthioadenosine phosphorylase (MTAP) deletion may serve as a potential biomarker for patient selection. The clinical translation of PRMT5 inhibitors is limited by hematological toxicity, lack of robust predictive biomarkers beyond MTAP and potential resistance from compensatory PRMT family members. It is key to clarify GI cancer-specific PRMT5 mechanisms and potentially develop optimized combination therapies in the future."

Journal • Review • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Hematological Disorders • Hepatocellular Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CTNNB1 • CXCL8 • EGFR • GPX4 • MTAP • MYC • PRMT5 • SLC7A11 • SMAD4 • TGFB1

Autophagy alterations in KRAS-mutant colorectal cancer following PRMT5 inhibition (AACR 2026) - "This study evaluates the mechanism of autophagy induction under PRMT5 inhibition and the possible apoptotic transition.Methodology: Four CRC cell lines, HCT116, SW640 (KRAS mutant), HKE3, and LIM2405 (KRAS wild type), were treated with three inhibitors, EPZ015666 (EPZ), GSK3326595 (GSK), and AMG-193 (AMG), each at 0.5 µM, 1 µM, and 10 µM, and assessed at 24 h and 48 h. Western blot analysis was conducted for ATG5, BECLIN1, BRG1, LC3B, ULK1, and ACTIN (housekeeping) to quantify autophagy regulation. Across four CRC lines, PRMT5 inhibition enhanced autophagy signaling, significantly in KRAS-mutant backgrounds. AMG consistently caused the strongest activation across early and late autophagy markers, indicating potent disruption of PRMT5-regulated stress-response circuits. We are currently investigating the onset of apoptosis under these treatment conditions by western blotting and gene expression by transcriptomics."

Colorectal Cancer • Oncology • Solid Tumor • ATG5 • BECN1 • KRAS • PRMT5 • SMARCA4

Elucidating and overcoming therapeutic resistance in esophageal adenocarcinoma (AACR 2026) - "This study aims to establish cisplatin-derived DTP(CDDP-DTP) and drug-resistant (CDDP-DR) EAC cell models to elucidate resistance mechanisms, identify therapeutic vulnerabilities, and develop strategies to overcome resistance and prevent recurrence in EAC. CDDP-DTP cells were generated by exposing EAC cells to the IC₈₀ of CDDP for four days, while CDDP-DR cells were developed via stepwise dose escalation based on the IC₅₀. Cytotoxic effects of compounds targeting ferroptosis, pyroptosis, and epigenetic regulation (RSL3, DMB, BIX-01294, and GSK3326595) were evaluated by MTS assays in four EAC cells (FLO-1, OE19, OE33, SK-GT-4)... This study successfully established CDDP-DTP and CDDP-DR models of EAC and revealed that targeting non-apoptotic, adaptive mechanisms can enhance therapeutic response. These findings lay the foundation for multi-omic characterization of resistant EAC populations and support exploration of non-apoptotic vulnerabilities to undermine recurrence and..."

Esophageal Adenocarcinoma • Esophageal Cancer • Oncology • Solid Tumor • ANXA5 • ATF4 • BCL2L1 • GPX4 • GSDMD

Comprehensive assay approaches for PRMT5 targeted drug discovery (AACR 2026) - "Here, we established comprehensive assay platforms for PRMT5-targeted drug discovery and validated them using five known inhibitors (LLY-283, JNJ-64619178, GSK591, EPZ015666, and GSK33326595). NanoBRET target engagement intracellular assay results indicated that the PRMT5 inhibitors engaged with the PRMT5/MEP50 complex within one hour of incubation in live HEK293 cells, and Western blot confirmed inhibition of histone H4R3me2s methylation, a key substrate of PRMT5, in MV4-11, Jeko-1, 22RV1, and PC3 cancer cell lines. Collectively, these platforms enable identification, optimization, and mechanistic characterization of PRMT5 inhibitors, accelerating development of selective and potent therapeutic candidates."

Hematological Malignancies • Oncology

Targeting PRMT5 enhances ferroptosis in B-cell lymphomas (AACR 2026) - "Moreover, the combination of DMF and GSK3326595 exhibited a significant synergistic effect...In summary, we demonstrate that targeting PRMT5 through pharmacological inhibition and genetic knockdown sensitizes DLBCL and MCL cells to DMF-induced lipid peroxidation and ferroptosis. These findings provide a rationale for developing a new therapeutic strategy that induces ferroptotic cell death to treat lymphoma patients with relapsed or refractory disease."

B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • GPX4 • PRMT5 • SLC7A11

Manganese-potentiated cGAS-STING activation with ATM/PRMT5 inhibition remodels the immunosuppressive microenvironment in osteosarcoma via bone-targeted delivery. (PubMed, Bioact Mater) - "To overcome these hurdles, we developed a bone-targeted, glutathione (GSH)-responsive polymeric nanoparticle (NPALN/Mn-AP) that chelates manganese (Mn) and delivers an ATM inhibitor (AZD0156) and a PRMT5 inhibitor (GSK3326595). By functionalizing this nanoplatform with alendronate (ALN) into NPALN/Mn-AP, we achieve preferential accumulation in bone tumors...In vivo studies demonstrate that NPALN/Mn-AP significantly inhibits OS progression and boosts systemic immune responses. This dual-action, bone-specific nanotherapeutic platform synchronized DNA-repair inhibition and Mn-enhanced immune-stimulation, offering a promising new approach for effective osteosarcoma treatment."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • STING

PRMT5 inhibition sensitizes B-cell lymphoma cells to ferroptosis. (PubMed, Leukemia) - "Notably, combined treatment with the PRMT5 inhibitor GSK3326595 and DMF synergistically enhances anti-tumor activity in a patient-derived xenograft (PDX) model. These findings reveal a previously unrecognized PRMT5-ATF5-SLC7A11 axis that drives ferroptosis resistance in B-cell lymphomas and provide a strong rationale for targeting PRMT5 to potentiate ferroptosis-based therapies in relapsed or refractory disease."

Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Metabolic Disorders • Non-Hodgkin’s Lymphoma • Oncology • ATF4 • ATF5 • PRMT5 • SLC7A11

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

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

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

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 • CAAP1 • CDKN2A • MTAP

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

Preclinical Evaluation of 68Ga-Labeled GSK3326595 for PRMT5 Expression with microPET-CT in Pan-Cancer. (PubMed, Mol Pharm) - "This research demonstrates that [68Ga]Ga-DOTA-FZ-P5R enables rapid imaging of PRMT5-positive tumors. The probe has significant potential to enable individualized and precise diagnosis in patients with PRMT5-positive tumors, define an optimal treatment window, assess therapeutic efficacy, and serve as a predictive imaging modality for tumor resistance."

Journal • Pan tumor • Preclinical • Oncology • PRMT5

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