EPZ015666 / GSK, Ipsen - LARVOL DELTA

Inhibition of Protein Arginine Methyltransferase 5 attenuates Dialysis-Related Peritoneal Fibrosis via Suppression of Angiogenesis and Inflammatory State. (PubMed, Clin Sci (Lond)) - "Genetic PRMT5 inhibition attenuated histopathological damage, extracellular matrix (ECM) deposition, angiogenesis and inflammatory infiltration induced by high-glucose PD fluid or chlorhexidine gluconate (CG), thereby improving peritoneal transport function...Furthermore, pharmacological inhibition of PRMT5 using selective PRMT5 inhibitor EPZ015666 also exhibited therapeutic efficacy in vivo. Mechanistically, our data implicates a PRMT5 mediated inflammation-angiogenesis axis in PF progression. Collectively, our findings establish PRMT5 as a pivotal, druggable epigenetic regulator in dialysis-related PF and provide a compelling rationale for clinical development of PRMT5-targeted strategies to prevent PF."

Journal • Diabetes • Fibrosis • Immunology • Inflammation • PRMT5

PRMT5 promotes psoriatic inflammation through mediating dimethylation of p65 in keratinocytes. (PubMed, Mol Med) - "These findings establish a PRMT5-p65 regulatory axis wherein PRMT5-mediated symmetric dimethylation at R158 and R166 stabilizes p65 by autophagy-mediated lysosomal degradation and amplifies NF-κB-driven inflammation in keratinocytes, identifying PRMT5 as a potential therapeutic target in psoriasis."

Journal • Dermatology • Immunology • Inflammation • Psoriasis • IL23A • PRMT5 • RELA

PRMT5 inhibition promotes cross-species spermatogonia expansion and suppresses differentiation. (PubMed, Cell Regen) - "Mechanistically, EPZ015666 exerted this effect by inhibiting the enzymatic active site of PRMT5. These findings suggest that PRMT5 inhibition could provide a novel strategy for culturing human SSCs in vitro."

Journal • Infertility • Sexual Disorders • Transplantation

PRMT5 inhibition suppresses the PI3K/AKT pathway to attenuate vascular smooth muscle cell pathological phenotype in intracranial aneurysm. (PubMed, Front Neurol) - "EPZ015666 inhibits the PI3K/AKT pathway to promote VSMC phenotype switching from synthetic phenotype to contractile phenotype, thereby attenuating IA progression. However, this study is limited by the use of male-only rats a relatively small sample size, which may restrict the generalizability of the findings."

Journal • Cardiovascular • Vascular Neurology • ELANE • MMP9 • SPP1

Inactivation of PRMT5 by PARP Inhibitors Confers High Susceptibility in MTAP-Deficient Cancers. (PubMed, Cancers (Basel)) - "MTAP-deficient tumors exhibited increased vulnerability to olaparib in vivo, and combined treatment with olaparib plus MTDIA or EPZ015666 produced improved therapeutic outcomes compared with olaparib alone. These findings identify PARP inhibitors as a potential therapeutic strategy for MTAP-deficient tumors through targeted inactivation of PRMT5 and support further evaluation of PARP inhibitor-based combination therapies in this molecular context."

Journal • Oncology • Solid Tumor • MTAP

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

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

Investigating the therapeutic potential of a nanocrystal PRMT5 inhibitor in pancreatic ductal adenocarcinoma (AACR 2026) - "Among these, our patented compound, PR5-LL-CM01 (CM01), has shown superior anti-tumor efficacy and reduced toxicity in PDAC models compared to the commercially available PRMT5 inhibitor EPZ015666...We hypothesize that CM01 NC more effectively inhibits PRMT5-mediated NF-κB signaling and associated oncogenic processes than unformulated CM01, and that it synergizes with gemcitabine (Gem) to suppress PDAC progression...We are now transitioning to in vivo studies to evaluate the pharmacokinetics and therapeutic efficacy of CM01 NC, both as a monotherapy and in combination with Gem, using PDAC models. This study may establish CM01 NC, alone or with Gem, as a promising therapeutic strategy, and could lay the foundation for clinical development of CM01 NC-based treatments for PDAC."

Oncology • Pancreatic Ductal Adenocarcinoma • CXCL8 • PRMT5 • TNFA

Enhancing CD8+ T Cells Infiltration Through the Protein Arginine Methyltransferase 5 (PRMT5)/CXCL10 Axis Restricts Cervical Cancer Progression. (PubMed, Biomolecules) - "Furthermore, the therapeutic efficacy of the selective PRMT5 inhibitor EPZ015666 was evaluated in a cervical cancer xenograft mouse model...In summary, these findings elucidate a novel mechanism whereby PRMT5 depletion in cervical cancer cells triggers a CXCL10-mediated chemotactic response, enhancing CD8+ T cell infiltration and restricting tumor progression. Thus, our study provides compelling evidence supporting the potential targeting of PRMT5 as a viable immunotherapeutic strategy for cervical cancer."

Journal • Cervical Cancer • Oncology • Solid Tumor • CD8 • CXCL10 • CXCR3

Synergistic Effects of Type I PRMT1 and Type II PRMT5 Inhibitors Against Multiple Myeloma (ASH 2023) - "To address this hypothesis, we treated MM cell lines with two clinical trial inhibitors: GSK3368715 (GSK) and EPZ 015666 (EPZ), suppressing PRMT type I and type II inhibitor, respectively...Of note, we found a similar anti-MM effect when treating bortezomib-resistant MM cells with GSK and EPZ, indicating that PRMT type I and type II inhibitors potentially have a substantial clinical impact on relapsed MM...In summary, our preliminary data suggest that suppression of both PRMT type I and type II might provide a potential effective combination treatment for both newly diagnosed and relapsed MM patients. We're currently investigating the underling mechanisms of how PRMTs regulate MM pathology and validating the in vivo efficacy of combination treatment using patient-derived xenograft."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor • PRMT1

ID1 boosts antiviral immunity by countering PRMT5-mediated STING methylation. (PubMed, Cell Rep) - "The stimulator of interferon genes (STING) is a vital protein for the activation of the type I interferon signaling pathway. Importantly, EPZ015666, a selective PRMT5 inhibitor, substantially enhanced antiviral immune responses in vivo and in vitro. These findings unveil an unreported regulatory mechanism in which ID1 and PRMT5 modulate STING activity and highlight EPZ015666 as a promising therapeutic candidate for antiviral interventions."

Journal • Infectious Disease • ID1 • STING

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

Cardiac-specific overexpression of PRMT5 exacerbates pressure overload-induced hypertrophy and heart failure. (PubMed, J Biomed Sci) - "The gain-of-function of PRMT5 in cardiomyocytes exacerbates pressure overload-induced cardiac hypertrophy and left ventricular systolic dysfunction, at least partially, through p300 methylation and histone acetyltransferase activation."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • PRMT5

PRMT5 Inhibitor EPZ015666 Decreases the Viability and Encystment of Entamoeba invadens. (PubMed, Molecules) - "In agreement with these findings, EPZ015666 reduced trophozoite viability and encystment. Therefore, EiPRMT5 is a potential target for inhibiting the spread of amebiasis."

Journal

Arginine demethylation of Serine/Arginine-rich splicing factor 1 enhances miRNA enrichment in small extracellular vesicles derived from pancreatic ductal adenocarcinoma cells. (PubMed, FASEB J) - "Treatment of PDAC cells with the protein arginine methyltransferase inhibitors AMI-5 and EPZ015666, but not with the phosphorylation inhibitor SRPIN340, selectively enhanced the level of sEV miR-1246, a miRNA known to be highly enriched in PDAC sEVs...Interestingly, the binding of SRSF1 to miR-1246 was significantly reduced in PDAC cells overexpressing the mutant SRSF1, which was further confirmed using purified wild-type and the mutant SRSF1 proteins. We demonstrate that arginine demethylation of SRSF1 reduces SRSF1-miRNA binding in PDAC cells and enhances selective sEV miRNA enrichment, providing novel insight into SRSF1-mediated sEV miRNA enrichment in PDAC cells and opening up new avenues of investigation on the biology and function of extracellular vesicles in PDAC."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • MIR1246

Exploring the Clinical Translation of Synthetic Lethality, PRMT5 Inhibitors in MTAP-Deleted Cancers: A Scoping Review (ISPOR-EU 2024) - P1/2 | "Notably, six oral PRMT5 inhibitors—MRTX1719, AG-270, AMI, LLY-238, HLCL-61, and EPZ015666 demonstrated significant antitumor activity in MTAP-deleted tumours in mouse xenograft models...Among the 25 clinical trials, two PRMT5 inhibitors, AMG193 (NCT05975073) and TNG908 (NCT05275478) are currently in Phase 1/2 trials targeting MTAP-null solid tumours. There is compelling evidence supporting the initial stages of drug development aimed at PRMT5 in MTAP-deleted cancers. Additional research is required to clarify molecular mechanisms and improve the clinical viability of this SL combination."

Clinical • Review • Synthetic lethality • Oncology • Solid Tumor • BRCA • MTAP

Three novel epigenetic-modifying compounds identified as HIV latency-reversing agents in Ghana (ASTMH 2024) - "The lead compounds were further screened in CD4+ T cells of four individuals living with HIV on suppressive ART.We identified five positive hits (MC1568, Abexinostat, Pracinostat, EPZ2015666, CXC6258-HCL) from the J.LAT 10.6 cell culture system with GFP-positive cells (20-91%). These compounds effectively reactivated latent HIV-1 in vitro and induced HIV expression ex vivo. Our findings suggest that these LRAs hold promise for reactivating latent HIV in individuals living with the virus."

Human Immunodeficiency Virus • Infectious Disease • CD4

Methylation of KSHV vCyclin by PRMT5 contributes to cell cycle progression and cell proliferation. (PubMed, PLoS Pathog) - "Remarkably, knockdown or pharmaceutical inhibition (using EPZ015666) of PRMT5 inhibited the cell cycle progression and cell proliferation of KSHV latently infected tumor cells...We also show that the methylation of vCyclin by PRMT5 positively regulates the phosphorylate retinoblastoma protein (pRB) pathway. Taken together, our findings reveal an important regulatory effect of PRMT5 on vCyclin that facilitates cell cycle progression and proliferation, which provides a potential therapeutic target for KSHV-associated malignancies."

Journal • Eye Cancer • Kaposi Sarcoma • Oncology • Retinal Disorders • Sarcoma • Solid Tumor • CCND2 • CDK6 • IL6 • PRMT5

Inhibition of PRMT5 moderately suppresses prostate cancer growth in vivo but enhances its response to immunotherapy. (PubMed, Cancer Lett) - "Inspired by the surprising finding that PRMT5 negatively correlates with tumor immune infiltration and transcriptionally suppresses an immune-gene program, we further show that although PRMT5 inhibitor (PRMT5i) EPZ015666 or anti-PD-1 immunotherapy alone exhibits limited antitumor effects, combination of PRMT5i with anti-PD-1 displays superior efficacy in inhibiting castration-resistant PCa (CRPC) in vivo. Finally, to expand the potential use of PRMT5i through a synthetic lethality concept, we also perform a global CRISPR/Cas9 knockout screen to unravel that many clinical-grade drugs of known oncogenic pathways can be repurposed to target CRPC when used in combination with PRMT5i at low doses. Collectively, our findings establish a rationale to exploit PRMT5i in combination with immunotherapy or other targeted therapies to treat aggressive PCa."

IO biomarker • Journal • Preclinical • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • PRMT5

PRMT5 activates lipid metabolic reprogramming via MYC contributing to the growth and survival of mantle cell lymphoma. (PubMed, Cancer Lett) - "Moreover, PRMT5 inhibitors including SH3765 and EPZ015666 worked through blocking SREBP1/2 and FASN expression in MCL. Furthermore, PRMT5 was significantly associated with MYC expression in 105 MCL samples and the GEO database (GSE93291). CRISPR MYC knockout indicated PRMT5 can promote MCL outgrowth by inducing SREBP1/2 and FASN expression through the MYC pathway."

Journal • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Metabolic Disorders • Non-Hodgkin’s Lymphoma • Oncology • FASN • MYC • PRMT5

Fibroblast-specific PRMT5 deficiency suppresses cardiac fibrosis and left ventricular dysfunction in male mice. (PubMed, Nat Commun) - "Finally, treatment with EPZ015666 significantly improves pressure overload-induced cardiac fibrosis and dysfunction. These findings suggest that PRMT5 regulates TGF-β/Smad3-dependent fibrotic gene transcription, possibly through histone methylation crosstalk, and plays a critical role in cardiac fibrosis and dysfunction."

Journal • Preclinical • Cardiovascular • Fibrosis • Heart Failure • Immunology • SMAD3 • TGFB1 • WDR5

Genetic screen identified PRMT5 as a neuroprotection target against cerebral ischemia. (PubMed, Elife) - "Encouraged by the above observation, mice were treated with middle cerebral artery occlusion with the PRMT5 inhibitor EPZ015666 and found that PRMT5 inhibition sustains protection against neuronal death in vivo. Together, these findings revealed a novel epigenetic mechanism of PRMT5 in cerebral ischemia and uncovered a potential target for neuroprotection."

Journal • Cardiovascular • Ischemic stroke • PRMT5

Epigenetic Regulation of Vascular Smooth Muscle Cell Phenotypic Switch and Neointimal Formation by PRMT5 (AHA 2023) - "Our results identify PRMT5 as a novel regulator in VSMC phenotypic switch and suggest that inhibition of PRMT5 may represent an effective therapeutic strategy for proliferative vascular diseases."

Atherosclerosis • Cardiovascular • Dyslipidemia • Hypertension • PRMT5

Epigenetic regulation of vascular smooth muscle cell phenotypic switch and neointimal formation by PRMT5. (PubMed, Cardiovasc Res) - "Our results identify PRMT5 as a novel regulator in VSMC phenotypic switch and suggest that inhibition of PRMT5 may represent an effective therapeutic strategy for proliferative vascular diseases."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Hypertension • PRMT5

Regulative role of miR-770-5p on PRMT5-EGFR axis in TNBC: focus on miR-770-5p / PRMT5 interaction and EGFR signal regulation (EACR 2023) - "The affect of PRMT5 inhibitor EPZ015666 on proliferation was analyzed by IncuCyte realtime imaging system...ConclusionOur previous findings and this study will enable us to explore the role of miR-770-5p in breast cancer in broader aspect. It is thought that reducing the expression of PRMT5, which is highly expressed in breast cancer, by miR-770-5p may provide inhibition of EGFR signal, and elucidation of this mechanism will add a new dimension to TNBC potential treatment approaches."

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