LLY-283 / Eli Lilly - LARVOL DELTA

PRMT5 inhibition sensitizes glioblastoma tumor models to temozolomide. (PubMed, Res Sq) - "Background: Despite multi-model therapy of maximal surgical resection, radiation, chemotherapy, and tumor-treating fields, glioblastoma patients show dismal prognosis. In vivo , LLY-283 and TMZ combination significantly curbed the tumor growth and prolonged the survival of tumor-bearing mice. Concomitant treatment of LLY-283 and TMZ has significantly greater antitumor efficacy, suggesting that PRMT5 inhibition and TMZ combination could be a new therapeutic strategy for glioblastoma."

Journal • Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CASP3 • CASP7 • HRD • PRMT5

Targeting epigenetic deregulation in pancreatic cancer via Protein Arginine Methyltransferase 5 (PRMT5) inhibition as a promising therapeutic strategy (LCC 2025) - "Patient-derived cell line models of PDAC were screened using cytotoxicity assays with various concentrations of SAM-competitive (LLY-283) and MTA-cooperative (MRTX-1719) PRMT5 inhibitor. Moreover, using 3D tumour cell-cancer associated fibroblast (CAF) co-culture assays, we showed no direct effects of PRMT5 targeting on CAF contractility and matrix remodelling; however, inhibition of PRMT5 as a monotherapy or combination therapy with MAT2A or PARP inhibitor significantly reduced cancer cell invasion in 3D organotypics model. Our ongoing work focuses on understanding the biological determinants, including gene expression and methylation signatures, and mechanisms behind PRMT5 inhibitor response and potential synergy that may allow broader clinical application."

Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • HRD • MAT2A • MTAP • PRMT5

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

PRMT5 modulates T cell proliferation in glioblastoma tumor microenvironment (SNO 2024) - " We inhibited PRMT5 using small molecule inhibitor (LLY283) or PRMT5 target specific siRNA in patient-derived primary GBM neurospheres (GBMNS) and assessed the T-cell proliferation and MDSC induction by flow cytometry... Our results suggests that PRMT5 inhibition increases T-cell proliferation potentially by blocking MDSC induction. Further studies are underway to understand the nexus between PDL-1/IL-6 and modulation of MDSC/T-cell activation in the context of PRMT5 status in glioblastoma and their potential impact on the anti-tumorigenic effect in an in vivo GBM model."

Biomarker • IO biomarker • Tumor microenvironment • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CD4 • IL6

Targeting PRMT5 enhances the radiosensitivity of tumor cells grown in vitro and in vivo. (PubMed, Sci Rep) - "Treatment of mice with LLY-283 decreased tumor PRMT5 activity and significantly enhanced the radiation-induced growth delay. These results suggest that PRMT5 is a tumor selective target for radiosensitization."

Journal • Preclinical • Tumor cell • Oncology • PRMT5

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

Mapping the knowledge domains of medical textiles: A review. (PubMed, Medicine (Baltimore)) - "Totally 2839 papers have been retrieved and collected from the core database of Web of Science™...Finally, the co-occurrence analysis of keywords is also performed using VOSviewer and CiteSpace. The connection between various disciplines in the research field is revealed, so that the scientific development history, the research hotspots, and main research directions in the field can be traced."

Journal • Review

Inhibition of histone methyltransferase PRMT5 attenuates cisplatin-induced hearing loss through the PI3K/Akt-mediated mitochondrial apoptotic pathway. (PubMed, J Pharm Anal) - "CUT&Tag-qPCR analysis demonstrated that inhibition of PRMT5 in HEI-OC1 cells reduced the accumulation of H4R3me2s/H3R8me2s marks at the promoter region of the Pik3ca gene, thus activating the expression of Pik3ca. These findings suggest that PRMT5 inhibitors have strong potential as agents against cisplatin-induced ototoxicity and can lay the foundation for further research on treatment strategies of hearing loss."

Epigenetic controller • Journal • Otorhinolaryngology • PI3K • PIK3CA • PRMT5

Inhibitors of the enzyme Arginine Methyltransferase (PRMT) are identified as radiosensitizers in glioblastoma cells through a chemical screen using an epigenetic probe library (EACR 2023) - "To examine the combined effect various PRMT inhibitors and RT, cell viability was measured with CellTiterGlo™ and colony formation assays in U373 GBM cells treated with 4 Gy radiation dose and different PRMT inhibitors (MS023, MS049, SGC707, and LLY283). However, the relationship between PRMT inhibition and RT response remains to be characterized.ConclusionTogether, our study ascribes a role for PRMTs in regulating the RT response of glioblastoma cells, adding to the recently emerging functions of these enzymes in cancer. The effects of PRMTi on the transcriptome of the glioblastoma cells as well as the DNA damage response will be investigated to decipher the specific roles PRMTs play in the context of RT in glioblastoma."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Screening non-small cell lung cancer organoids with epigenetic probes (AACR 2023) - "Library was provided by Structural Genomics Consortium (www.thesgc.org) and contained compounds targeting a variety of protein domains some of which had activity on acetylation, methylation, histone de-methylation etc. CellTiter-Glo assay was performed to measure cell survival. Among the epigenetic probe compounds tested on 26 models, LLY 283 (PRMT5 inhibitor) showed the most significant effect on inhibition of cell growth in 69% of organoid models(18/26) with suppression of >=40% as compared to the DMSO control... A screen using epigenetic compounds on NSCLC patient-derived organoids revealed sensitivity to PRMT5 inhibitor in 69% of the organoid models tested. Further investigation will explore the mechanisms that are associated with sensitivity to PRMT5 inhibition."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PRMT5

Targeting prmt5 inhibits DNA repair and enhances the radiosensitivity of GBM cells (AACR 2023) - "Because a 1h LLY-283 pretreatment was sufficient for the inhibition of DSB repair and enhanced radiosensitivity, it appears that the radiosensitization was primarily the result of altered chromatin function rather than changes in gene expression due to alternative mRNA splicing. Altogether, these results suggest targeting PRMT5 as a potential strategy for enhancing the radiosensitivity of GBMs."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • PRMT5

Risk prediction model of peritoneal seeding in advanced gastric cancer: A decision tool for diagnostic laparoscopy. (PubMed, Eur J Surg Oncol) - "This nomogram provides effective risk estimates of peritoneal seeding from gastric cancer and can facilitate individualized decision-making regarding the selective use of diagnostic laparoscopy."

Journal • Metastases • Anesthesia • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

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

PRMT5 inhibition sensitizes glioblastoma neurospheres to temozolomide (SNO 2022) - " We depleted PRMT5 activity, in vitro, using target-specific siRNA or LLY-283 and combined these with TMZ treatment. Overall, PRMT5 inhibition sensitized GBMNS to TMZ and enhanced TMZ-related DNA damage and cytotoxicity. These findings support further development of this potential therapeutic combination."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor • CASP3 • CASP7 • H2AX • HRD • PRMT5 • RUVBL1

Elderly Age, Female Gender, and Prolonged Hemodialysis Stay Related With Pathological Body Composition Bioimpedance in Ecuadorian Hemodialysis Patients (KIDNEY WEEK 2022) - "Results Totally 283 patients, 55% were male, age 56,5(±15,years), HD time 4.5(±3.6,years)...See image 1. Conclusion BIS offered accurate water distribution and body composition information which could help to identify earlier disturbances in elderly Ecuadorian HD patients with prolonged HD stays and women which were linked with protein-energy wasting syndrome findings and increased risk of mortality."

Clinical • Cachexia • Renal Disease • Sarcopenia

LLY-283 inhibits proliferation and metastasis of head and neck squamous cell carcinoma by targeting PRMT5 (PubMed, Shanghai Kou Qiang Yi Xue) - "LLY-283 inhibits the expression of PRMT5 and Ki-67, thereby decreases the proliferation and metastasis of HNSCC and the ability to form transplanted tumors in nude mice, exerting anti-tumor effects."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Transplantation • PRMT5

A PRMT5 inhibitor protects against noise-induced hearing loss by alleviating ROS accumulation. (PubMed, Ecotoxicol Environ Saf) - "Furthermore, we showed that LLY-283 could increase the expression level of p-AKT in the SGNs. The underlying mechanism involves alleviation of ROS accumulation and activation of the PI3K/AKT pathway, indicating that LLY-283 might be a potential candidate for therapeutic intervention against NIHL."

Journal • Otorhinolaryngology • CASP3 • CASP7 • PRMT5

Correlating atmospheric pressure and temperature with Meniere attack. (PubMed, Auris Nasus Larynx) - "Atmospheric pressure and temperature are correlated with the onset of Meniere attack. Summer season has a higher incidence of Meniere attack than winter season, likely because low atmospheric pressure in summer may aggravate endolymphatic hydrops, especially when accompanied by typhoons in the northwest Pacific region."

Journal • Otorhinolaryngology

Inhibition of PRMT5 Attenuates Cerebral Ischemia/Reperfusion-Induced Infammation and Pyroptosis Through Suppression of NF-κB/NLRP3 Axis. (PubMed, Neurosci Lett) - "Finally, we observed that treatment of LLY-283 alleviated neurological deficits and reduced infarct volume in the MCAO/R mice. Taken together, PRMT5 may be a potential therapeutic target for cerebral I/R injury."

Journal • Immunology • Inflammation • Neuroblastoma • Oncology • Reperfusion Injury • Solid Tumor • IL6 • NLRC5 • NLRP3 • PRMT5

Explore the effect of LLY-283 on the ototoxicity of auditory cells caused by cisplatin: A bioinformatic analysis based on RNA-seq. (PubMed, J Clin Lab Anal) - "LLY-283 can rescue cisplatin-induced auditory cell apoptosis injury. LLY-283 can inhibit the increase in PRMT5 expression induced by cisplatin."

Journal • Otorhinolaryngology • PRMT5

[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 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

Et3B/Et2AlCl/O2-Mediated Radical Coupling Reaction between α-Alkoxyacyl Tellurides and 2-Hydroxybenzaldehyde Derivatives. (PubMed, Chem Asian J) - "The reaction chemo- and stereoselectively forged the hindered C-C bond between two oxygen-functionalized carbons at ambient temperature. The method was applied to the preparation of 12 coupling adducts with three to six contiguous stereocenters and to the concise synthesis of an antitumor compound, LLY-283."

Journal • Oncology

An Epigenetic Screen Identifies PRMT5 As a Target for Inhibition of FLT3-ITD AML Cell Growth in Combination with Tyrosine Kinase Inhibitors (ASH 2019) - "We further show that the combination of PRMT5 inhibitors (GSK591, LLY283 5μM) with AC220 (500pM) resulted in increased inhibition of cell proliferation and increased induction of apoptosis compared to TKI alone, p<0.05 (Figure 1a-c). In conclusion, our studies using an unbiased approach have identified PRMT5 inhibition as a novel and selective approach to enhance targeting of FLT3-ITD AML cells in combination with FLT3 TKI. These results support our ongoing studies to evaluate the cellular and molecular mechanisms underlying these combinatorial effects, and to determine the translational therapeutic potential of this combination using primary patient samples and mouse models."

Combination therapy • DNMT3A • EZH2 • FLT3 • IDH1 • MLL

Discovery of SAM competitive and non-nucleoside derivative PRMT5 inhibitors with potent antitumor activity (ACS-Sp 2019) - "...Although the mechanism of PRMT5 related to tumorigenesis is still unclear, S-adenosylmethionine (SAM), as the co-factor of PRMT5, plays essential roles in the processes of methylating a variety of cytoplasmic and nuclear substrates that are involved in tumorigenesis...One targets the enzyme substrate site, whose binding is dependent of SAM or SAM analogues’ binding, such as EPZ015666; the other targets co-factor site, such as LLY-283, which binds directly to SAM pocket and the majority of inhibitors in this type are nucleoside based...The binding affinity and efficacy have been increased by 25 folds and 40 folds respectively. Furthermore, the binding and enzymatic assays show that our compounds are SAM competitive PRMT5 inhibitors."