Protein Arginine Methyltransferase 5 Inhibition Research Articles

Protein Arginine Methyltransferase 1: A Multi-Purpose Player in the Development of Cancer and Metabolic Disease

Protein arginine methyltransferase 1 (PRMT1) is the main PRMT family member involved in the formation of monomethylarginine and asymmetric dimethylarginine on its protein substrates. Many protein substrates of PRMT1 are key mediators of cell proliferation and oncogenesis. As such, the function of PRMT1 has been most prominently investigated in the context of cancer development. However, recent in vitro and in vivo studies have highlighted that PRMT1 may also promote metabolic disorders. With the current review, we aim to present an in-depth overview of how PRMT1 influences epigenetic modulation, transcriptional regulation, DNA damage repair, and signal transduction in cancer. Furthermore, we summarize the current knowledge regarding the role of PRMT1 in metabolic reprogramming, lipid metabolism, and glucose metabolism and describe the association of PRMT1 with numerous metabolic pathologies such as obesity, liver disease, and type 2 diabetes. It has become apparent that inhibiting the function of PRMT1 will likely serve as the most beneficial therapeutic approach, since several PRMT1 inhibitors have already been shown to exert positive effects on both cancer and metabolic disease in preclinical settings. However, pharmacological PRMT1 inhibition has not yet been shown to be therapeutically effective in clinical studies.

PRMT5 Inhibition Reduces Hyperinflammation in a Murine Model of Secondary Hemophagocytic Lymphohistiocytosis (HLH).

Hemophagocytic lymphohistiocytosis (HLH) is a rare but aggressive and potentially lethal hyperinflammatory syndrome characterized by pathologic immune activation and excessive production of proinflammatory cytokines leading to tissue damage and multisystem organ failure. There is an urgent need for the discovery of novel targets and development of therapeutic strategies to treat this rare but deadly syndrome. Protein Arginine Methyltransferase 5 (PRMT5) mediates T cell-based inflammatory responses, making it a potential actionable target for the treatment of HLH. Using CPG-1826 and anti-IL10R antibody, we induced murine secondary HLH in vivo with a marked expansion of splenic myeloid cell subsets and concurrent reduction of T and NK cell populations. PRMT5 expression was significantly upregulated in splenic T and NK lymphocytes as well as monocytes and dendritic cells in mice with HLH (p<0.05). Treatment with PRT382, a potent and selective PRMT5 inhibitor, significantly reduced physical signs of secondary HLH, including splenomegaly, hepatomegaly and anemia (p<0.0001 in each case), when compared to untreated mice. Inflammatory cytokines known to drive hyperinflammation in HLH, including IFNγ and IL-6 were reduced to healthy levels with PRT382 treatment (p>0.999 for both). PRT382 treatment also reduced the expansion of myeloid cell populations (p<0.0001) in mice with HLH, compared to untreated mice, while restoring T and NK cell numbers (p<0.001 for both). These results identify PRMT5 as a promising target for the management of secondary HLH and justify further exploration in this and other models of hyperinflammation.

PRMT5 inhibition has a potent anti-tumor activity against adenoid cystic carcinoma of salivary glands

BackgroundAdenoid cystic carcinoma (ACC) is a rare glandular malignancy, commonly originating in salivary glands of the head and neck. Given its protracted growth, ACC is usually diagnosed in advanced stage. Treatment of ACC is limited to surgery and/or adjuvant radiotherapy, which often fails to prevent disease recurrence, and no FDA-approved targeted therapies are currently available. As such, identification of new therapeutic targets specific to ACC is crucial for improved patients’ outcomes.MethodsAfter thoroughly evaluating the gene expression and signaling patterns characterizing ACC, we applied PandaOmics (an AI-driven software platform for novel therapeutic target discovery) on the unique transcriptomic dataset of 87 primary ACCs. Identifying protein arginine methyl transferase 5 (PRMT5) as a putative candidate with the top-scored druggability, we next determined the applicability of PRMT5 inhibitors (PRT543 and PRT811) using ACC cell lines, organoids, and patient derived xenograft (PDX) models. Molecular changes associated with response to PRMT5 inhibition and anti-proliferative effect of the combination therapy with lenvatinib was then analyzed.ResultsUsing a comprehensive AI-powered engine for target identification, PRMT5 was predicted among potential therapeutic target candidates for ACC. Here we show that monotherapy with selective PRMT5 inhibitors induced a potent anti-tumor activity across several cellular and animal models of ACC, which was paralleled by downregulation of genes associated with ACC tumorigenesis, including MYB and MYC (the recognized drivers of ACC progression). Furthermore, as a subset of genes targeted by lenvatinib is upregulated in ACC, we demonstrate that addition of lenvatinib enhanced the growth inhibitory effect of PRMT5 blockade in vitro, suggesting a potential clinical benefit for patients expressing lenvatinib favorable molecular profile.ConclusionTaken together, our study underscores the role of PRMT5 in ACC oncogenesis and provides a strong rationale for the clinical development of PRMT5 inhibitors as a targeted monotherapy or combination therapy for treatment of patients with this rare disease, based on the analysis of their underlying molecular profile.

Discovery of Potent, Highly Selective, and Orally Bioavailable MTA Cooperative PRMT5 Inhibitors with Robust In Vivo Antitumor Activity.

Protein arginine methyltransferase 5 (PRMT5), which catalyzes the symmetric dimethylation of arginine residues on target proteins, plays a critical role in gene expression regulation, RNA processing, and signal transduction. Aberrant PRMT5 activity has been implicated in cancers and other diseases, making it a potential therapeutic target. Here, we report the discovery of a methylthioadenosine (MTA) cooperative PRMT5 inhibitor. Compound 20 exhibited strong antiproliferation activity in multiple MTAP-deleted cancer cell lines, excellent selectivity over MTAP wild-type cell lines, as well as satisfactory oral pharmacokinetic properties over various preclinical species. Notably, compound 20 demonstrated a dose-dependent reduction of symmetric dimethylarginine (SDMA) expression in the LU99 cell line and robust in vivo antitumor activity in the LU99 subcutaneous model.

PRMT1-mediated BRD4 arginine methylation and phosphorylation promote partial epithelial-mesenchymal transformation and renal fibrosis.

Bromodomain-containing protein 4 (BRD4) plays a vital role in fibrosis of various organs. However, the underlying mechanism of BRD4 in renal fibrosis remains unclear. To construct invitro and invivo models of renal fibrosis, TCMK-1 cells were subjected to TGF-β1 treatment and mice were subjected to UUO surgery and adenine induction. IP assay was used for arginine asymmetric dimethylation (ADMA) level, ubiquitination degradation of Snail, and acetylation level of Snail test. Co-IP was used to validate the interactions of BRD4, protein arginine methyltransferase-1 (PRMT1), and Snail. HE staining and Masson staining were used for morphological examination of renal tissue. BRD4 was abnormally overexpressed during renal fibrosis. TGF-β1-induced fibrosis and partial epithelial-mesenchymal transition (pEMT) could be inhibited by BRD4 silencing. PRMT1 mediated ADMA level of BRD4 to enhance BRD4 phosphorylation and its protein stability. Snail protein degradation was attenuated by BRD4 overexpression in an acetylation-dependent manner in TCMK-1 cells. Furthermore, PRMT1 inhibitor abolished BRD4 overexpression-induced fibrosis and pEMT in TGF-β1-treated TCMK-1 cells and Snail overexpression reversed BRD4 silencing-induced inhibition of fibrosis and pEMT. What's more, the reduction of BRD4 arginine methylation inhibited BRD4 phosphorylation and Snail expression to alleviate renal fibrosis in UUO surgery and adenine induction mice. Collectively, PRMT1-mediated BRD4 arginine methylation and phosphorylation promoted pEMT and renal fibrosis through regulation of Snail expression.

Discovery of PRMT5 N-Terminal TIM Barrel Ligands from Machine-Learning-Based Virtual Screening.

Protein arginine methyltransferase 5 (PRMT5), which symmetrically dimethylates cytosolic and nuclear proteins, has been demonstrated as an important cancer therapeutic target. In recent years, many advanced achievements in PRMT5 inhibitor development have been made. Most PRMT5 inhibitors in the clinical trial focus on targeting the C-terminal catalytic domain, whereas developing small molecules to interrupt the PRMT5/pICLn (methylosome subunit) protein-protein interface is also of great importance for inhibiting PRMT5. Here, we describe a machine-learning-based virtual screening method and use this novel pipeline to screen small-molecule inhibitors of the PRMT5/pICLn interaction. 18 compounds were manually selected for experimental testing. One compound, Z319334062, showed surface plasmon resonance-binding affinity to the target (K D = 21.5 μM) and dose-dependently inhibited symmetric dimethylation levels in patient-derived glioblastoma cell lines.

PRMT5 Inhibitor EPZ015666 Decreases the Viability and Encystment of Entamoeba invadens.

Protein arginine methyltransferase 5 (PRMT5) is an enzyme that produces monomethyl arginine (MMA) and symmetric dimethyl arginine (sDMA), post-translational modifications that regulate several cellular processes, including stage conversion in parasitic protozoans. Entamoeba histolytica, the etiologic agent of human amebiasis, has two stages in its life cycle, the trophozoite, which is the replicative form, and the cyst, corresponding to the infective phase. The study of the molecular mechanisms that regulate differentiation in this parasite has been overdue because of a lack of efficient protocols for in vitro encystment. For this reason, Entamoeba invadens, a parasite of reptiles, has been used as a differentiation model system for the genus. Here, we demonstrated the presence of sDMA in E. invadens, which increases during encystment, and identified the PRMT5 of this microorganism (EiPRMT5). In addition, we performed 3D modeling of this enzyme, as well as its molecular docking with the PRMT5 inhibitor EPZ015666, which predicted the affinity of the drug for the active site of the enzyme. In agreement with these findings, EPZ015666 reduced trophozoite viability and encystment. Therefore, EiPRMT5 is a potential target for inhibiting the spread of amebiasis.

The PRMT5-splicing axis is a critical oncogenic vulnerability that regulates detained intron splicing.

Protein arginine methyltransferase 5 (PRMT5) is a promising cancer target, yet it's unclear which PRMT5 roles underlie this vulnerability. Here, we establish that PRMT5 inhibition induces a special class of unspliced introns, called detained introns (DIs). To interrogate the impact of DIs, we depleted CLNS1A, a PRMT5 cofactor that specifically enables Sm protein methylation. We found that many, but not all, cell lines are CLNS1A-dependent and established that loss of viability is linked to loss of Sm protein methylation and DI upregulation. Finally, we discovered that PRMT5-regulated DIs, and the impacted genes, are highly conserved across human, and also mouse, cell lines but display little interspecies conservation. Despite this, human and mouse DIs have convergent impacts on proliferation by affecting essential components of proliferation-regulating complexes. Together, these data argue that the PRMT5-splicing axis, including appropriate DI splicing, underlies cancer's vulnerability to PRMT5 inhibitors.

PRMT5-Mediated ALKBH5 Methylation Promotes Colorectal Cancer Immune Evasion via Increasing CD276 Expression.

Numerous diseases have been connected to protein arginine methylations mediated by protein arginine methyltransferase 5 (PRMT5). Clinical investigations of the PRMT5-specific inhibitor GSK3326595 are currently being conducted, and the results are promising for preventing cancers. However, the detailed mechanism of PRMT5 promoting colorectal cancer (CRC) malignant progression remains unclear. Here, we found that PRMT5 directly catalyzes AlkB homologue 5 (ALKBH5) symmetric dimethylation at the R316 residue (meR316-ALKBH5), which enhances TRIM28-mediated ALKBH5 ubiquitination degradation. Then, an ALKBH5 decrease attenuates ALKBH5-mediated m6A demethylation on the CD276 transcript 3' untranslated region, which increases CD276 messenger RNA stability and its expression in CRC cells. Furthermore, a CD276 expression increase facilitates CRC immune evasion by inhibiting cytotoxic T-cell functions. Moreover, we revealed that PRMT5-mediated meR316-ALKBH5 activates CD276 transcription by increasing its messenger RNA m6A modification to increase CRC immune evasion invitro and invivo. Furthermore, we consistently showed a strong association between meR316-ALKBH5 and poor outcomes in patients with CRC. 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.

Magnesium-dependent-protein phosphatase 1B regulates the protein arginine methyltransferase 5 through the modulation of myosin phosphatase.

Dysregulation of the expression levels and the activity of kinases/phosphatases is an intrinsic hallmark of tumor transformation and progression, as either as a primary cause or consequence. The myosin phosphatase (MP)/protein arginine methyltransferase 5 (PRMT5)/histone (H4) pathway is an oncogenic signaling pathway downregulating the gene expression of tumor suppressors. However, the upstream regulators of the pathway are unknown. We show that the Mg2+-dependent protein phosphatase 1B (PP2Cb or PPM1B) interacts and regulates MP through the MYPT1 regulatory subunit, and this interplay results in the inactivation of the tumorigenic pathway driven by PRMT5. The phospho-Thr696 inhibitory residues of the MYPT1 regulatory subunit of MP was dephosphorylated by PPM1B. The inhibition of PPM1B by sanguinarine resulted in the deactivation of MP and the increased activity of PRMT5 leading to increased symmetric dimethylation of histone H4 in HeLa cells. The overexpression of the PPM1B had the opposite action. The overexpression of PPM1B decreased the colonization activity of HeLa cells through modulation of MP. Finally, human cervical carcinoma biopsies showed almost complete elimination of PPM1B compared to their healthy control counterparts. The phosphorylation of the inhibitory MYPT1pT696 and the regulatory PRMT5pT80 residues and the symmetric dimethylation of H4 were elevated in the cancer biopsies and it resulted in a decrease in retinoblastoma protein expression. The results indicate a tumor suppressor role of the PPM1B/MP axis via inhibition of PRMT5, thereby regulating gene expression through H4 arginine dimethylation. Collectively, PPM1B is a tumor suppressor and a possible tumor marker for cervical carcinoma.

Shedding light on imaging cancer research: Design and synthesis of 1, 8-naphthalimide-based PRMT5-targeted fluorescent ligands.

Protein Arginine Methyltransferase 5 (PRMT5) is an important player in breast cancer cell activity, and innovative fluorescent ligands targeting this enzyme offer revolutionary, real-time insights into its role in cancer progression, unlocking new avenues for diagnosis and treatment. This study introduces fluorescence-labeled PRMT5 ligands, highlighting their applications in visualizing PRMT5, monitoring enzymatic activity as well as studying toxicity. Herein, we describe the design, synthesis, and cellular imaging of a series of fluorescent ligands that target PRMT5. These ligands are based on the introduction of strong and selective PRMT5 inhibitors into various fluorophores using varied linkers. Among them, compound 7 at 10μM was shown to exhibit strong fluorescence signals against MCF-7 cells with IC50 values of 29nM. These advancements could significantly impact tumor treatment due to their ability to specify the target and visualize PRMT5 activity in real time, particularly in breast cancer research.

MRTX1719, an MTA-cooperative PRMT5 Inhibitor, Induces Cell Cycle Arrest and Synergizes With Oxaliplatin and Gemcitabine for Enhanced Anticancer Effects.

MRTX1719 is a novel protein arginine methyltransferase 5 (PRMT5) inhibitor that targets the PRMT5-5'-Methylthioadenosine (MTA) complex called MTA-cooperative PRMT5 inhibitor. MRTX1719 acts specifically on methylthioadenosine phosphorylase (MTAP)-deficient cancer cells; however, its mechanism of action remains unclear. This study aimed to clarify the effects of MRTX1719 on the cell cycle and its synergistic effects with other anticancer drugs. A cell cycle assay was conducted using fluorescence-activated cell sorting to examine the correlation between PRMT5 activity and cells in the G0/G1 phase. The synergistic effects of MRTX1719 and anticancer drugs were evaluated using the Combination Index (CI) and Bliss synergy score (BSS). The synergistic effect was also evaluated by knocking down the endogenous expression of MTAP in HCT116 cells with high MTAP expression. The cell cycle assay showed that the population of cells with reduced PRMT5 activity increased, and the administration of MRTX1719, an MTAP inhibitor, increased the population of cells in the G0/G1 phase. In the synergistic effect assay, oxaliplatin and gemcitabine demonstrated a CI <1 and a BSS >0, indicating a synergistic effect when administered alongside MRTX1719. MTAP knockdown also resulted in <1 in CI and >0 in BSS after the administration of oxaliplatin or gemcitabine with MRTX1719. MRTX1719 reduces PRMT5 activity, leading to cell cycle arrest by increasing the proportion of cells in the G0/G1 phase. Moreover, MRTX1719 exhibits synergistic anticancer effects with oxaliplatin and gemcitabine in MTAP-deficient cancer cells.

TMIC-76. PRMT5 MODULATES T CELL PROLIFERATION IN GLIOBLASTOMA TUMOR MICROENVIRONMENT

Abstract INTRODUCTION Glioblastoma, the most common malignant brain tumor, presents a significant obstacle because of its immunosuppressive tumor microenvironment, complicating standard treatment approaches. Protein Arginine Methyltransferase 5 (PRMT5) that regulates cellular functions by symmetrically dimethylating arginine residues is dysregulated in glioblastoma. Inhibiting PRMT5 induces apoptosis and senescence in the differentiated and undifferentiated glioblastoma tumor cells respectively. As PRMT5 is known to play an important role in immune cell response and T cell reprogramming, in this study we sought to probe the role of PRMT5 in the modulation of glioblastoma tumor immune response. METHODS 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. Further, we also probed for PDL-1 and IL-6 expression by ELISA and westernblot assays. RESULT: PRMT5 inhibition significantly increased CD4+ T-cell proliferation but the MDSC induction was suppressed. As PDL-1/IL-6 axis is known to play a significant role in both anti-tumorigenic T-cell proliferation and pro-tumorigenic MDSC induction, we probed for the expression of PDL-1 and IL-6. While PRMT5 blockade reduced PDL-1 expression, IL-6 expression was upregulated. CONCLUSION 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.

One stone two birds: Introducing piperazine into a series of nucleoside derivatives as potent and selective PRMT5 inhibitors

The protein arginine methyltransferase 5 (PRMT5) has emerged as potential target for the treatment of cancer. Many efforts have been made to develop potent and selective PRMT5 inhibitors targeting either S-adenosyl methionine (SAM) pocket or substrate binding pocket. Here, we rationally designed a series of nucleoside derivatives incorporated with piperazine as novel PRMT5 inhibitors occupying both pockets. The representative compound 36 exhibited highly potent PRMT5 inhibition activity as well as good selectivity over other methyltransferases. Further cellular experiments revealed that compound 36 potently reduced the level of symmetric dimethylarginines (sDMA) and inhibited the proliferation of MOLM-13 cell lines by inducing apoptosis and cell cycle arrest. Moreover, compound 36 had more favorable metabolic stability and aqueous solubility than JNJ64619178 (9). Meanwhile, it obviously suppressed the tumor growth in a MOLM-13 tumor xenograft model. These results clearly indicate that 36 is a highly potent and selective PRMT5 inhibitor worthy for further development.

SCR-7952, a highly selective MAT2A inhibitor, demonstrates synergistic antitumor activities in combination with the S-adenosylmethionine-competitive or the methylthioadenosine-cooperative protein arginine methyltransferase 5 inhibitors in methylthioadenosine phosphorylase-deleted tumors.

The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was found to elicit synthetic lethality in methylthioadenosine phosphorylase (MTAP)-deleted cancers, which occur in about 15% of all cancers. Here, we described a novel MAT2A inhibitor, SCR-7952 with potent and selective antitumor effects on MTAP-deleted cancers in both in vitro and in vivo. The cryo-EM data indicated the high binding affinity and the allosteric binding site of SCR-7952 on MAT2A. Different from AG-270, SCR-7952 exhibited little influence on metabolic enzymes and did not increase the plasma levels of bilirubin. A systematic evaluation of combination between SCR-7952 and different types of protein arginine methyltransferase 5 (PRMT5) inhibitors indicated remarkable synergistic interactions between SCR-7952 and the S-adenosylmethionine-competitive or the methylthioadenosine-cooperative PRMT5 inhibitors, but not substrate-competitive ones. The mechanism was via the aggravated inhibition of PRMT5 and FANCA splicing perturbations. These results indicated that SCR-7952 could be a potential therapeutic candidate for the treatment of MTAP-deleted cancers, both monotherapy and in combination with PRMT5 inhibitors.

First-in-human study of AMG 193, an MTA-cooperative PRMT5 inhibitor, in patients with MTAP-deleted solid tumors: results from phase I dose exploration

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) occurs in ∼10%-15% of solid tumors. AMG 193, a CNS-penetrant methylthioadenosine-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor, selectively induces synthetic lethality in MTAP-deleted tumor cells. Here, we report results of the completed monotherapy dose exploration evaluating AMG 193 in patients with MTAP-deleted solid tumors. In this first-in-human, multicenter, open-label, phase I study, patients with advanced CDKN2A-deleted and/or MTAP-deleted solid tumors received AMG 193 orally [once (o.d.) or twice (b.i.d.) daily] continuously in 28-day cycles. Primary objectives were safety and tolerability assessed by dose-limiting toxicities and determination of the maximum tolerated dose; secondary objectives included pharmacokinetics and preliminary antitumor activity measured by RECIST v1.1. As of 23 May 2024, 80 patients in dose exploration received AMG 193 at doses 40-1600 mg o.d. or 600 mg b.i.d. The most common treatment-related adverse events were nausea (48.8%), fatigue (31.3%), and vomiting (30.0%). Dose-limiting toxicities were reported in eight patients at doses ≥240 mg, including nausea, vomiting, fatigue, hypersensitivity reaction, and hypokalemia. The maximum tolerated dose was determined to be 1200 mg o.d. Mean exposure of AMG 193 increased in a dose-proportional manner from 40 mg to 1200 mg. Among the efficacy-assessable patients treated at the active and tolerable doses of 800 mg o.d., 1200 mg o.d., or 600 mg b.i.d. (n= 42), objective response rate was 21.4% (95% confidence interval 10.3% to 36.8%). Responses were observed across eight different tumor types, including squamous/non-squamous non-small-cell lung cancer, pancreatic adenocarcinoma, and biliary tract cancer. At doses ≥480 mg, complete intratumoral PRMT5 inhibition was confirmed in paired MTAP-deleted tumor biopsies, and molecular responses (circulating tumor DNA clearance) were observed. AMG 193 demonstrated a favorable safety profile without clinically significant myelosuppression. Encouraging antitumor activity across a variety of MTAP-deleted solid tumors was observed based on objective response rate and circulating tumor DNA clearance.

Abstract C063: Inhibition of PRMT5 reduces aggressiveness in basal-like pancreatic ductal adenocarcinoma

Abstract The basal-like pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive type of mesenchymal PDAC that resists treatment and has a poor prognosis. Understanding the mechanisms driving basal-like PDAC biology is crucial for unraveling the intricacies of PDAC plasticity and developing effective treatment strategies for this aggressive tumor. Recent studies from our laboratory have shown that protein arginine methyl transferase 5 (PRMT5) significantly contributes to PDAC plasticity and progression towards the basal-like subtype. Specifically, our data show that patients with high levels of PRMT5 expression have a worse outcome, thus arguing that PRMT5 plays a role in PDAC aggressiveness and outcome. Moreover, our experiments indicate that inhibiting PRMT5, either genetically or chemically, in basal-like PDAC cells induces the expression of epithelial markers like GATA6 and E-CADHERIN, suggesting that PRMT5 promotes mesenchymal features in PDAC. Using wound healing and transwell assays, we have demonstrated that pharmacological inhibition of PRMT5 significantly suppresses cell migration and invasion. Additionally, colony formation and cell proliferation are markedly reduced upon PRMT5 inhibition in basal-like PDAC. Collectively, these findings suggest that inhibiting PRMT5 can effectively constrain the aggressive cellular features characteristic of basal-like PDAC, such as cell proliferation, clonogenicity, and migration. Recent research indicates that PRMT5 preferentially methylates splicing factors in various cell types, implying that RNA splicing regulation is crucial to PRMT5’s role in enhancing tumor plasticity and aggressiveness. We are currently investigating whether PRMT5-mediated RNA splicing alterations contribute to the maintenance of the basal-like PDAC phenotype. These studies provide key evidence that PRMT5 is essential for maintaining the aggressive characteristics of basal-like PDAC, highlighting its potential as a therapeutic target for this challenging cancer subtype. Citation Format: Christina Wang, Zamira Guerra Soares, Dakarai Esgdaille, Stephano Spano Mello. Inhibition of PRMT5 reduces aggressiveness in basal-like pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C063.

AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients with MTAP-Deleted Cancers.

One of the most robust synthetic lethal interactions observed in multiple functional genomic screens has been the dependency on protein arginine methyltransferase 5 (PRMT5) in cancer cells with MTAP deletion. We report the discovery of the clinical stage MTA-cooperative PRMT5 inhibitor AMG 193, which preferentially binds PRMT5 in the presence of MTA and has potent biochemical and cellular activity in MTAP-deleted cells across multiple cancer lineages. In vitro, PRMT5 inhibition induces DNA damage, cell cycle arrest, and aberrant alternative mRNA splicing in MTAP-deleted cells. In human cell line and patient-derived xenograft models, AMG 193 induces robust antitumor activity and is well tolerated with no impact on normal hematopoietic cell lineages. AMG 193 synergizes with chemotherapies or the KRAS G12C inhibitor sotorasib in vitro and combination treatment in vivo substantially inhibits tumor growth. AMG 193 is demonstrating promising clinical activity, including confirmed partial responses in patients with MTAP-deleted solid tumors from an ongoing phase 1/2 study. Significance: AMG 193 preferentially inhibits the growth of MTAP-deleted tumor cells by inhibiting PRMT5 when in complex with MTA, thus sparing MTAP wild-type normal cells. AMG 193 shows promise as a targeted therapy in a clinically defined patient population.

Identification of PRMT5 as a therapeutic target in cholangiocarcinoma

BackgroundCholangiocarcinoma (CCA) is a very difficult-to-treat cancer. Chemotherapies are little effective and response to immune checkpoint inhibitors is limited. Therefore, new therapeutic strategies need to be identified.ObjectiveWe characterised the enzyme...

Methylation of KSHV vCyclin by PRMT5 contributes to cell cycle progression and cell proliferation.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA virus that encodes numerous cellular homologs, including cyclin D, G protein-coupled protein, interleukin-6, and macrophage inflammatory proteins 1 and 2. KSHV vCyclin encoded by ORF72, is the homolog of cellular cyclinD2. KSHV vCyclin can regulate virus replication and cell proliferation by constitutively activating cellular cyclin-dependent kinase 6 (CDK6). However, the regulatory mechanism of KSHV vCyclin has not been fully elucidated. In the present study, we identified a host protein named protein arginine methyltransferase 5 (PRMT5) that interacts with KSHV vCyclin. We further demonstrated that PRMT5 is upregulated by latency-associated nuclear antigen (LANA) through transcriptional activation. Remarkably, knockdown or pharmaceutical inhibition (using EPZ015666) of PRMT5 inhibited the cell cycle progression and cell proliferation of KSHV latently infected tumor cells. Mechanistically, PRMT5 methylates vCyclin symmetrically at arginine 128 and stabilizes vCyclin in a methyltransferase activity-dependent manner. 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.