EPZ015666 / GSK, Ipsen - LARVOL DELTA

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

New therapy for pancreatic cancer based on extracellular vesicles. (PubMed, Biomed Pharmacother) - "Therefore, we loaded the small EVs with two chemotherapeutic drugs (Temozolomide and EPZ015666) by direct incubation method and the amount of drug loaded was measured by high-performance liquid chromatography (HPLC). Moreover, the system is highly dependent on the drug structure and therefore RWP-1 small EVs were more efficient than RWP-1 small EVs. RWP-1 derived small EVs represent a promising drug delivery tool that can be further investigated in preclinical studies and its combination with PRMT5 inhibitor can be potentially developed in clinical trials for the treatment of PDAC."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • PRMT5

Glioblastoma-Derived Small Extracellular Vesicles: Nanoparticles for Glioma Treatment. (PubMed, Int J Mol Sci) - "After loading them with two different drugs, Temozolomide (TMZ) and EPZ015666, we observed a reduction in the total amount of drugs needed to trigger an effect on tumor cells. Moreover, we observed that GBM-derived small EVs, although with lower target specificity, can induce an effect on pancreatic cancer cell death. These results suggest that GBM-derived small EVs represent a promising drug delivery tool for further preclinical studies and potentially for the clinical development of GBM treatments."

Journal • Brain Cancer • CNS Tumor • Gastrointestinal Cancer • Glioblastoma • Glioma • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

(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

The PRMT5 inhibitor EPZ015666 is effective against HTLV-1-transformed T-cell lines in vitro and in vivo. (PubMed, Front Microbiol) - "Administration of EPZ015666 in both NSG xenograft and HTLV-1-infected humanized immune system (HIS) mice significantly improved survival outcomes. The cumulative findings of this study demonstrate that the epigenetic regulator PRMT5 is critical for the survival, transformation, and pathogenesis of HTLV-1, illustrating the value of this cellular enzyme as a potential therapeutic target for the treatment of ATL."

Journal • Preclinical • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Infectious Disease • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD4 • PRMT5

Adriamycin induces cardiac fibrosis in mice via PRMT5-mediated cardiac fibroblast activation. (PubMed, Acta Pharmacol Sin) - "Pretreatment with a specific PRMT5 inhibitor EPZ015666 (5 nM) or overexpression of a catalytically inactive mutant of PRMT5, PRMT5(E444Q), reduced PRMT5-induced methylation of Smad3, thus suppressing PRMT5-mediated cardiac fibroblast activation in vitro. Furthermore, ADR activated cardiac fibroblasts was depending on autocrine TGF-β1. Taken together, our results demonstrate that PRMT5 promotes ADR-induced cardiac fibrosis via activating cardiac fibroblasts, suggesting that it may be a potential therapeutic target of ADR-caused cardiotoxicity."

Journal • Preclinical • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • PRMT5 • SMAD3 • TGFB1

Magnetic-Driven Hydrogel Microrobots Selectively Enhance Synthetic Lethality in MTAP-Deleted Osteosarcoma. (PubMed, Front Bioeng Biotechnol) - " In this study, EPZ015666, a PRMT5 inhibitor, was selected as the synthetic lethality drug... Our magnetic-driven drug delivery system could carry synthetic lethality drugs. Meanwhile, the selective inhibition of this system could be easily controlled by programming the strength of the magnetic field."

Journal • Synthetic lethality • Inflammatory Arthritis • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • MTAP • PRMT5

Discovery of novel PRMT5 inhibitors bearing a methylpiperazinyl moiety. (PubMed, Future Med Chem) - "Methods & We synthesized a series of methylpiperazinyl derivatives as novel PRMT5 inhibitors that were achieved by scaffold-hopping from EPZ015666 by virtual screening followed by rational drug design...Further proteomics analysis revealed that 43g remarkably reduced the global arginine dimethylation level in a cellular context. This work provides new chemical templates for future structural optimization of PRMT5-related cancer treatments."

Journal • Oncology • PRMT5

PRMT5-mediated RNF4 methylation promotes therapeutic resistance of APL cells to AsO by stabilizing oncoprotein PML-RARα. (PubMed, Cell Mol Life Sci) - "Acute promyelocytic leukemia (APL) is a hematological malignancy driven by the oncoprotein PML-RARα, which can be treated with arsenic trioxide (AsO) or/and all-trans retinoic acid. The combination of EPZ015666 with AsO shows synergistic effects on AsO-induced differentiation of bone marrow cells from APL mice, as well as on apoptosis and differentiation of primary APL cells from APL patients. These findings provide mechanistic insight into the function of PRMT5 in APL pathogenesis and demonstrate that inhibition of PRMT5, alone or in combination with AsO, might be a promising therapeutic strategy against APL."

Journal • Acute Promyelocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • PML • PRMT5 • RARA

Arginine methyltransferase PRMT5 methylates and destabilizes Mxi1 to confer radioresistance in non-small cell lung cancer. (PubMed, Cancer Lett) - "More importantly, pharmacological inhibition of PRMT5 with the specific inhibitor EPZ015666 leads to extraordinary radiosensitization in vitro and in vivo in lung cancer. Altogether, our data indicate that PRMT5 methylates and destabilizes Mxi1 to confer radioresistance, suggesting that PRMT5 may be a promising radiosensitization target in non-small cell lung cancer."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • PRMT5