pemrametostat (GSK3326595) / Ipsen - LARVOL DELTA

MTA-cooperative PRMT5 inhibitors enhance T cell-mediated antitumor activity in MTAP-loss tumors. (PubMed, J Immunother Cancer) - "Collectively, our results provide a strong rationale and mechanistic insights for the clinical development of MRTX1719-based IO combinations in MTAP-loss tumors."

Journal • Oncology • MTAP

MTA-cooperative PRMT5 inhibitors enhance T cell-mediated antitumor activity in MTAP-loss tumors (J Immunother Cancer) - "GSK3326595 significantly suppresses PRMT5 activity in tumors and T cells regardless of the MTAP status. However, MRTX1719, a methylthioadenosine-cooperative PRMT5 inhibitor, exhibits tumor-specific PRMT5 inhibition in MTAP-loss tumors with limited immunosuppressive effects....In addition, MRTX1719 sensitizes MTAP-loss tumor cells to the killing of tumor-reactive T cells. Combining MRTX1719 and anti-PD-1 leads to superior antitumor activity in mice bearing MTAP-loss tumors."

Preclinical • Oncology

Phase I/II study of the clinical activity and safety of GSK3326595 in patients with myeloid neoplasms. (PubMed, Ther Adv Hematol) - P1/2 | "The safety profile was broadly consistent with other published PRMT5 inhibitor studies. ClinicalTrials.gov: NCT03614728."

Journal • P1/2 data • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Fatigue • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • SRSF2 • U2AF1

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

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

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 • CDKN2A • MTAP

PRMT5 is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer. (PubMed, Nat Commun) - "Furthermore, treatment with the PRMT5 inhibitor pemrametostat and a selective ER degrader fulvestrant synergistically inhibits growth of ER+/RB-deficient cell-derived and patient-derived xenografts. These findings highlight dual ER and PRMT5 blockade as a potential therapeutic strategy to overcome resistance to CDK4/6i in ER+/RB-deficient breast cancer."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Sarcoma • Solid Tumor • ER • FUS • RB1

METEOR-1: An Open-label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK3326595 in Participants With Solid Tumors and Non-Hodgkin's Lymphoma (clinicaltrials.gov) - P1 | N=288 | Completed | Sponsor: GlaxoSmithKline | Active, not recruiting ➔ Completed

Trial completion • Brain Cancer • Hematological Malignancies • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Triple Negative Breast Cancer • Urothelial Cancer

MST2 methylation by PRMT5 inhibits Hippo signaling and promotes pancreatic cancer progression. (PubMed, EMBO J) - "Methylation suppresses MST2 autophosphorylation and kinase activity by blocking its homodimerization, thereby inactivating Hippo signaling pathway in pancreatic cancer. Moreover, we also show that the specific PRMT5 inhibitor GSK3326595 re-activates the dysregulated Hippo signaling pathway and inhibits the growth of human pancreatic cancer xenografts in immunodeficient mice, thus suggesting potential clinical application of PRMT5 inhibitors in pancreatic cancer."

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

Combined inhibition of MTAP and MAT2a mimics synthetic lethality in tumor models via PRMT5 inhibition. (PubMed, J Biol Chem) - "Combination MTDIA and AG-270 treatment differs from direct inhibition of PRMT5 by GSK3326595 by avoiding toxicity caused by cell death in the normal gut epithelium induced by the PRMT5 inhibitor. The combination of MTAP and MAT2a inhibitors expands this synthetic lethal approach to include MTAP cancers, especially the remaining 98% of CRCs without the MTAP genotype."

Journal • Preclinical • Synthetic lethality • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MAT2A • MDM4 • MTAP

Therapeutic Advantage of Targeting PRMT5 in Combination with Chemotherapies or EGFR/HER2 Inhibitors in Triple-Negative Breast Cancers. (PubMed, Breast Cancer (Dove Med Press)) - "The drug combinations were performed using proliferation and colony formation assays on TNBC cell lines that were sensitive or resistant to EPZ015938, a PRMT5 inhibitor that has been evaluated in clinical trials. The chemotherapies analyzed were cisplatin, doxorubicin, camptothecin, and paclitaxel. The targeted therapies tested were erlotinib (EGFR inhibitor), neratinib (EGFR/HER2/HER4 inhibitor) and tucatinib (HER2 inhibitor)...We noticed that synergy can be obtained in TNBC cell lines that were resistant to PRMT5 inhibition alone. Altogether, our data highlight the therapeutic potential of targeting PRMT5 using combinatorial strategies for the treatment of subsets of TNBC patients."

Combination therapy • Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ERBB4 • PRMT5

MTA-cooperative PRMT5 inhibitors are efficacious in MTAP-deleted malignant peripheral nerve sheath tumor models (SNO 2023) - P1/2 | " The proliferation effects of MTA-cooperative PRMT5 inhibitors, TNG908 or TNG462, and a SAM-cooperative PRMT5 inhibitor, GSK3326595, on MTAP-deleted and MTAP-intact MPNST cell lines were determined using CellTiter-Glo (CTG) assays. The clinical stage MTA-cooperative PRMT5 inhibitors TNG908 (NCT05275478) and TNG462 (NCT05732831) are efficacious in MPNST models in vitro and in vivo and are therefore promising therapeutic agents for patients with MTAP-deleted MPNST."

Preclinical • Brain Cancer • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • CDKN2A • MTAP

Antitumor effects of PRMT5 inhibition in sarcomas. (PubMed, Cancer Res Commun) - "We then used the potent and selective GSK3326595 (GSK595) compound to investigate the antitumor effect of the pharmacologic inhibition of PRMT5 in vitro via MTT, apoptosis, cell cycle, clonogenicity, and proliferation assays...The present study demonstrated that PRMT5 regulates STS cell metabolism and thus represents a potential therapeutic target for STS. Additional studies in diverse sarcoma subtypes will be essential to confirm and expand upon these findings."

Journal • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • PRMT5

PRMT5 and CDK4/6 inhibition result in distinctive patterns of alternative splicing in melanoma. (PubMed, PLoS One) - "We performed full-length mRNA sequencing on CHL1 and A375 melanoma cell lines treated with the CDK4/6 inhibitor palbociclib and the PRMT5 inhibitor GSK3326595 and analysed data for differential gene expression and differential pre-mRNA splicing induced by these agents. Although PRMT5 inhibition and CDK4/6 inhibition induced common RNA splicing events and gene expression profiles, the majority of events induced by CDK4/6 inhibition were distinct. Our findings indicate CDK4/6 has the ability to regulate alternative splicing in a manner that is distinct from PRMT5 inhibition, resulting in divergent changes in gene expression under each therapy."

Journal • Melanoma • Oncology • Solid Tumor

Inhibiting PRMT5 induces DNA damage and increases anti-proliferative activity of Niraparib, a PARP inhibitor, in models of breast and ovarian cancer. (PubMed, BMC Cancer) - "These data demonstrate that inhibition of PRMT5 induced signatures of DNA damage in models of breast and ovarian cancer. Furthermore, combination with the PARP inhibitor, Niraparib, resulted in increased anti-tumor activity in vitro and in vivo. Overall, these data suggest inhibition of PRMT5 as a mechanism to broaden and enhance the clinical application of PARP inhibitors."

Journal • Oncology • Ovarian Cancer • Solid Tumor • PRMT5 • RAD51 • TP53BP1

PRMT5 is an actionable target in CDK4/6 inhibitor-resistant ER+/Rb-deficient breast cancer (AACR 2023) - "In accordance with the abnormal accumulation of pSer2 Pol II at TSS, pemrametostat treatment also resulted in an increased Pol II pausing index and an enrichment of intron retention splicing variants. Finally, therapeutic inhibition of PRMT5 with pemrametostat synergized with fulvestrant (a selective ER degrader) against growth of ER+/Rb-deficient breast cancer cell line- and patient-derived xenografts in mice, suggesting this combination as a novel therapeutic strategy for ER+/Rb-deficient metastatic breast cancers."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Sarcoma • Solid Tumor • Triple Negative Breast Cancer • ER • FUS • PRMT5 • RB1

PRMT5 regulates the chemoresistnace of ovarian cancer cells (AACR 2023) - "In this study, we first found that PRMT5 was upregulated in paclitaxel (PTX)-resistant ovarian cancer cells compared with non-resistant cancer cells. Then, we determined the oncogenic role of PRMT5 in chemoresistant ovarian cancer by using its potent and selective inhibitor, GSK3326595...Moreover, PRMT5 inhibitor significantly decreased the number of sphere formation and attenuated the stem cell-like properties in PTX-resistant ovarian cancer cells. Therefore, our study suggests that PRMT5 is a powerful target to overcome resistance to conventional chemotherapy for the treatment strategy in ovarian cancer."

Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • PRMT5

PH020-803: an MTA-cooperative and brain-penetrable PRMT5 inhibitor that selectively targets MTAP-deleted tumors (AACR 2023) - "Based on the synthetic lethality interaction, an MTA cooperative PRMT5 inhibitor has the potential to selectively target MTAP-deleted tumors and avoid hematologic toxicity of substrate-competitive (such as GSK3326595) or SAM-competitive (such as JNJ64619178) PRMT5 inhibitors. A pair of HCT116 isogenic cell lines (MTAP-/- and MTAP+/+) were used to determine the effects of PH020-803 on cell proliferation and intracellular symmetric dimethylarginine (SDMA) content. The present data suggest that PH020-803 is an MTA-cooperative and brain-penetrable PRMT5 inhibitor that selectively targets MTAP-deleted tumors."

Brain Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • ABCB1 • CD34 • MTAP • PRMT5

Combination therapeutic strategy with type I PRMT inhibition in cancer treatment (AACR 2023) - "We validated the synergistic effects and mechanisms of combined treatment with a type I PRMT inhibitor and a PRMT5 inhibitor (JNJ-64619178, GSK3326595/EPZ015938 or an in-house PRMT5i) using cell-based assays and in vivo studies...In vitro and in vivo studies revealed that inhibitors of type I PRMT and MAT2A (AG-270) dosing combination indeed exhibited stronger anti-cancer activity than mono-treatment...In vivo, the combination of type I PRMT inhibitor with different FLT3 inhibitors (Gilteritinib, Midostaurin, or CTS2016) led to deeper antitumor responses in a variety of FLT3-ITD AML models. Taken together, these findings support the co-administration of type I PRMT inhibitor with various therapies including epigenetic reprogramming, cancer metabolism modulation, or targeted therapies for receptor tyrosine kinases, which could benefit cancer patients as a promising therapeutic strategy."

Combination therapy • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • FLT3 • MAT2A • PRMT1 • PRMT5

PRMT5 inhibition induces pro-inflammatory macrophage polarization and increased hepatic triglyceride levels without affecting atherosclerosis in mice. (PubMed, J Cell Mol Med) - "PRMT5 inhibition by low-dose GSK3326595 treatment does not affect the inflammatory state or atherosclerosis susceptibility of Western-type diet-fed LDL receptor knockout mice, while it induces hepatic triglyceride accumulation. Severe side effects in liver, i.e. development of non-alcoholic fatty liver disease, should thus be taken into account upon chronic treatment with this PRMT5 inhibitor."

Journal • Preclinical • Atherosclerosis • Cardiovascular • Dyslipidemia • Hepatology • Inflammation • Non-alcoholic Fatty Liver Disease • CD36 • FASN • IFNG • PRMT5

A Phase I/II Study to Investigate the Safety and Clinical Activity of the Protein Arginine Methyltransferase 5 Inhibitor GSK3326595 in Subjects with Myelodysplastic Syndrome and Acute Myeloid Leukemia (ASH 2019) - P1/2; "Part 2B is a single-arm investigation of safety and efficacy of GSK3326595 plus 5-azacitidine in participants with newly diagnosed high-risk MDS. As of 1 August 2019, recruitment is ongoing across six centers in the United States and Canada; ten participants have been enrolled, all into Part 1. ClinicalTrials.gov identifier: NCT03614728 Study is funded by GlaxoSmithKline"

Clinical • P1/2 data

A phase I, open-label, dose-escalation study to investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of GSK3326595 in subjects with solid tumors and non-Hodgkin's lymphoma (AACR 2017) - "Up to 138 subjects may be enrolled in Part 2, and cohorts may be closed early for futility. As of 17 January 2017, recruitment is ongoing across four centers (USA, Canada, Netherlands, and France), and four subjects have been enrolled into the dose-escalation cohorts."

P1 data • Biosimilar • Bladder Cancer • Breast Cancer • Genito-urinary Cancer • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Triple Negative Breast Cancer • Urothelial Cancer

METEOR-1: A phase I study of the safety and efficacy of the protein arginine methyltransferase 5 (PRMT5) inhibitor GSK3326595 in advanced solid tumors (ESMO 2022) - P1 | "b N=14 efficacy evaluable pop. c Confirmed responses (CR or PR) based on RECIST 1.1 (solid tumors) or Lugano (NHL) criteria."

Clinical • P1 data • Adenoid Cystic Carcinoma • Brain Cancer • Breast Cancer • Genito-urinary Cancer • Glioblastoma • 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 • Triple Negative Breast Cancer • PRMT5

OTT-19-06: A Phase II Window of Opportunity Trial of PRMT5 Inhibitor, GSK3326595, in Early Stage Breast Cancer (clinicaltrials.gov) - P2 | N=40 | Completed | Sponsor: Ottawa Hospital Research Institute | Not yet recruiting ➔ Completed | N=60 ➔ 40 | Trial completion date: Dec 2022 ➔ Aug 2022 | Trial primary completion date: Dec 2022 ➔ Aug 2022

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CD4 • CD8 • ER • FOXP1 • HER-2 • PGR • PRMT5 • TP53

Design, Synthesis and Biological Evaluation of Novel and Potent Protein Arginine Methyltransferases 5 Inhibitors for Cancer Therapy. (PubMed, Molecules) - "Herein, a series of tetrahydroisoquinoline (THIQ) derivatives were designed and synthesized as PRMT5 inhibitors using GSK-3326595 as the lead compound...Furthermore, compound 20 possesses acceptable pharmacokinetic profiles and displays considerable in vivo antitumor efficacy in a MV-4-11 xenograft model. Taken together, compound 20 is an antitumor compound worthy of further study."

Journal • Acute Myelogenous Leukemia • Oncology • PRMT5