GSK3368715 / Ipsen - LARVOL DELTA

The transition from myelodysplastic neoplasm to secondary acute myeloid leukemia is revealed by molecular analysis, while functional drug screening demonstrates novel sensitivity patterns with clinical implication (ASH 2025) - "There are only a limited number of agentsthat are FDA approved for treatment of MDS including BCL2 and IDH inhibitors, hypomethylating agents(HMAs), ESAs, luspatercept and imetelstat...For MDS patients, weidentified the most effective agents with the proportion of sensitive samples noted in parentheses:mitoxantrone (100%), olutasidenib (78%), venetoclax (67%), dinaciclib (67%), trametinib (67%), olaparib(56%), GSK3368715 (56%), pacritinib (44%), lenalidomide (44%), fludarabine (55%), tasquinimod (44%),veliparib (44%). For sAML patients, we identified lenalidomide, olutasidenib, GSK3368715 have high DSSsin all tested samples, while fludarabine, fedratinib, tasquinimod, trametinib, veliparib, mitoxantrone andolaparib have high DSSs in 75% of the AML samples...Cancer Research 2024), and our samples included SF3B1 and U2AF1 mutations.Summary This study of the transition of MDS to sAML highlights molecular changes and reveals new drugsensitivity with agents that could be..."

Biomarker • Clinical • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • CD34 • FLT3 • JAK2 • NRAS • PTPN11 • SF3B1 • U2AF1

Targeting type I PRMTs in ALS: in vivo evaluation of MS023 and GSK3368715 in TDP43Q331K and SOD1G93A mice (ALS-MND 2025) - "Higher CNS exposures of MS023 and GSK3368715, were achieved using elacridar (50 mg/kg, PO), a P-glycoprotein inhibitor, which was therefore used in all subsequent studies. Both compounds were well-tolerated up to 50 mg/kg, with higher doses causing weight loss. In TDP43Q331K mice, plasma ADMA levels were elevated relative to wild-type controls and were reduced by GSK3368715, but not by MS023."

Preclinical • Plasma NfL • TARDBP

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

Therapeutic potential of PRMT1 as a critical survival dependency target in multiple myeloma. (PubMed, BMC Cancer) - "Treatment with the Type I PRMT inhibitor GSK3368715 resulted in a dose-dependent reduction in cell survival across a panel of MM cell lines...This was supported by Reverse Phase Protein Array (RPPA) analyses, which revealed a significant reduction in levels of proteins associated with cell cycle regulation and DDR pathways. Overall, our findings indicate that MM cells critically depend on PRMT1 for survival, highlighting the therapeutic potential of PRMT1 inhibition in treating MM."

Journal • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • PRMT1

Development of a manufacturing route towards GSK3368715, a type I PRMT inhibitor (ACS-Fall 2025) - "Utilization of this strategic disconnection allowed elimination of 4 problematic reactions, doubled the overall yield, and drastically reduced cost of goods. Additionally, the scope of alkenylation was evaluated through multivariate HTE studies, which facilitated identification of a general protocol for the direct C-H alkenylation of multiple heterocyclic classes."

B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Solid Tumor

Epidrug screening identifies type I PRMT inhibitors as modulators of lysosomal exocytosis and drug sensitivity in cancers. (PubMed, Cell Death Dis) - "Two type I PRMT inhibitors, MS023 and GSK3368715, showed synergy with cisplatin, reduced cell viability, and inhibited lysosomal exocytosis without altering lysosomal biogenesis gene expression. These inhibitors also synergized with other lysosome-sequestered drugs, indicating a broader application in overcoming drug resistance. Analysis of patient data further linked lower type I PRMT levels to better responses, highlighting their potential as combination therapy candidates to enhance chemotherapy efficacy and improve cancer survival rates."

Journal • Oncology

Discovery of a first-in-class protein arginine methyltransferase 1 (PRMT1) degrader for nonenzymatic functions studies. (PubMed, Eur J Med Chem) - "Among them, only GSK3368715 advanced to clinical trials but was discontinued in phase I due to inadequate efficacy and thrombosis toxicity. Notably, as anticipated, CM112 could target PRMT1's nonenzymatic function by downregulating the stability of the orphan receptor TR3, an effect not observed with the PRMT1 inhibitor MS023, that is in consistence with the previous findings. Taken together, CM112 represents a valuable tool for elucidating the unknown, methyltransferase-independent roles of PRMT1 in disease progression and pave the way for developing more potent and drug like PRMT1 degraders in future."

Journal • Cardiovascular • Hematological Disorders • Oncology • Solid Tumor • Thrombosis • PRMT1 • PRMT3

Therapeutic Potential of PRMT1 as a Critical Survival Dependency Target in Multiple Myeloma. (PubMed, bioRxiv) - "Treatment with the Type I PRMT inhibitor GSK3368715 resulted in a dose-dependent reduction in cell survival across a panel of MM cell lines...This was supported by Reverse Phase Protein Array (RPPA) analyses, which revealed a significant reduction in levels of proteins associated with cell cycle regulation and DDR pathways. Overall, our findings indicate that MM cells critically depend on PRMT1 for survival, highlighting the therapeutic potential of PRMT1 inhibition in treating MM."

Journal • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • PRMT1

Development of a Manufacturing Route Towards GSK3368715 (ACS-Fall 2024) - "Utilization of this strategic disconnection allowed elimination of 4 problematic reactions, doubled the overall yield, and drastically reduced cost of goods. Additionally, the scope of alkenylation was evaluated through multivariate HTE studies, which facilitated identification of a general protocol for the direct C-H alkenylation of multiple heterocyclic classes."

Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Towards the Targeted Protein Degradation of PRMT1. (PubMed, ChemMedChem) - "The phase 1 clinical trial for GSK3368715, the first PRMT1 inhibitor to enter the clinic, was terminated early due to a lack of clinical efficacy, extensive treatment-emergent effects, and dose-limiting toxicities...Suitable cell permeability and target engagement were shown for selected candidates by the detection of downstream effects of PRMT1 inhibition and by a NanoBRET assay for E3-ligase binding, however the candidates did not induce PRMT1 degradation. This paper is the first reported investigation of PRMT1 for targeted protein degradation and provides hypotheses and insights to assist the design of PROTACs for PRMT1 and other novel target proteins."

Journal • Oncology • Targeted Protein Degradation • CRBN • PRMT1

PRMT1 is a critical dependency in clear cell renal cell carcinoma with roles in post- transcriptional regulation and DNA damage response (AACR 2024) - "Among the several promising targets identified, a particularly favorable inhibition profile was noted for MS023, an inhibitor of the type I protein arginine methyltransferase family (PRMT1/3/4/6 and 8)...This growth inhibition was corroborated using an additional type I PRMT compound, GSK3368715...Our data suggests that inhibition of PRMT1 inhibits processing of mRNA transcripts, compromises DDR mechanisms, leading to an accumulation of double stranded breaks, cytostasis and cell death. Thus PRMT1 represents a viable therapeutic target in ccRCC."

Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • BAP1 • PBRM1 • PRMT1 • SETD2 • VHL

PRMT1 acts as a suppressor of MHC-I and anti-tumor immunity. (PubMed, Cell Rep) - "Indeed, PRMT1 knockout or pharmacological targeting of type I PRMT with the clinical inhibitor GSK3368715 enhances Ifnγ-induced MHC-I expression through elevated STAT1 expression and activation, while re-introduction of PRMT1 in PRMT1-deficient cells reverses this effect. Importantly, loss of PRMT1 enhances the efficacy of anti-PD-1 immunotherapy, and The Cancer Genome Atlas analysis reveals that PRMT1 expression in human melanoma is inversely correlated with expression of human leukocyte antigen molecules, infiltration of CD8+ T cells, and overall survival. Taken together, we identify PRMT1 as a negative regulator of anti-tumor immunity, unveiling clinical type I PRMT inhibitors as immunotherapeutic agents or as adjuncts to existing immunotherapies."

IO biomarker • Journal • Melanoma • Oncology • Solid Tumor • CD8 • IFNG • PRMT1 • STAT1

Direct Heterocycle C-H Alkenylation via Dual Catalysis Using a Palladacycle Precatalyst: Multifactor Optimization and Scope Exploration Enabled by High-Throughput Experimentation. (PubMed, J Org Chem) - "In all, 192 substrate combinations were tested with a hit rate of approximately 40% and 24 isolated examples. Importantly, this method was applied to prepare a key intermediate in the synthesis of GSK3368715 on multigram scale."

Journal

Phase 1 study of GSK3368715, a type I PRMT inhibitor, in patients with advanced solid tumors. (PubMed, Br J Cancer) - P1 | "Based on higher-than-expected incidence of TEEs, limited target engagement at lower doses, and lack of observed clinical efficacy, a risk/benefit analysis led to early study termination."

Journal • Metastases • P1 data • Cardiovascular • Oncology • Pulmonary Embolism • Respiratory Diseases • Solid Tumor

PRMT1 inhibition promotes ferroptosis sensitivity via ACSL1 upregulation in acute myeloid leukemia. (PubMed, Mol Carcinog) - "Additionally, the GSK3368715 treatment reduced the abundance of H4R3me2a, the main histone methylation modification mediated by PRMT1, in both genome-wide and ACSL1 promoter regions. Overall, our results demonstrated a previously unknown role of the PRMT1/ACSL1 axis in ferroptosis and suggested the potential value and applications of the combination of PRMT1 inhibitor and ferroptosis inducers in AML treatment."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

"Select projects targeting synthetic lethality TNG908 MRTX1719 SKL27969 AMG 193 AG-270 IDE397 JNJ-64619178 PRT543 PRT811 RP-6306 GSK3326595 GSK3368715 PF-06939999 JBI-778 TNG462 ISM020 AGX323 AT101/ AT201 @JacobPlieth @evaluatepharma https://t.co/74gBPzNLcn https://t.co/5Um0uV9GAB" (@BRAINCURES)

Synthetic lethality

Full year and fourth quarter 2021 (GSK Press Release) - "R&D pipeline - GSK3326595 and GSK3368715 (PRMT5 inhibitor and Type I PRMT inhibitor): Removed from the Phase I pipeline due to prioritisation within the synthetic lethal portfolio (termination of in-license agreement with Epizyme will be effective on 16 March 2022)."

Licensing / partnership • Pipeline update • Oncology

Inhibiting Type I arginine methyltransferase activity promotes the T cell mediated antitumor immune response. (PubMed, Cancer Immunol Res) - "Type I protein arginine methyltransferases (PRMTs) have been implicated in human cancers and a Type I PRMT inhibitor, GSK3368715, has recently entered clinical trials in solid and hematological malignancies...In immunocompetent mouse tumor models including a model of T cell exclusion, representing a common mechanism of PD1 resistance in humans, Type I PRMT inhibition increased T cell infiltration, produced durable responses dependent on CD8+ T cells and enhanced efficacy of anti-PD1 therapy. These data suggest Type I PRMT inhibition can potentiate an antitumor immunity in refractory settings."

IO biomarker • Journal • Hematological Disorders • Hematological Malignancies • Oncology • CD8

First Time in Humans (FTIH) Study of GSK3368715 in Participants With Solid Tumors and Diffuse Large B-cell Lymphoma (DLBCL) (clinicaltrials.gov) - P1; N=31; Completed; Sponsor: GlaxoSmithKline; Recruiting ➔ Completed; N=215 ➔ 31; Trial completion date: Jul 2022 ➔ Mar 2021; Trial primary completion date: Jul 2022 ➔ Mar 2021

Clinical • Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Diffuse Large B Cell Lymphoma • Gastrointestinal Cancer • Hematological Malignancies • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • ALK • CDKN2A • EML4 • MTAP

IDEAYA Biosciences Announces Submission of IND Application for MAT2A Development Candidate IDE397 with the U.S. FDA (PRNewswire) - "IDEAYA Biosciences, Inc...announced it has submitted an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) for the initiation of a Phase 1 clinical trial to evaluate IDE397, a small molecule methionine adenosyltransferase 2a (MAT2A) inhibitor, for the treatment of patients having solid tumors with methylthioadenosine phosphorylase (MTAP) deletion....IDEAYA will also present its proposed IDE397 Phase 1 clinical plan in MTAP-deleted solid tumors, including monotherapy and combination strategies, and discuss the combination rationale for IDE397 and GSK's Type I PRMT inhibitor GSK3368715."

Clinical protocol • IND • Oncology • Solid Tumor

Identification of hnRNP-A1 as a pharmacodynamic biomarker of type I PRMT inhibition in blood and tumor tissues. (PubMed, Sci Rep) - "Utilizing targeted mass spectrometry (MS), methods were developed to detect and quantitate changes in methylation of specific arginine residues on hnRNP-A1. This resulted in the development and validation of novel MS and immune assays useful for the assessment of GSK3368715 induced pharmacodynamic effects in blood and tumors that can be applied to GSK3368715 clinical trials."

Biomarker • Journal • PK/PD data • Oncology

Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss. (PubMed, Cancer Cell) - "Interestingly, deletion of the methylthioadenosine phosphorylase gene (MTAP) results in accumulation of the metabolite 2-methylthioadenosine, an endogenous inhibitor of PRMT5, and correlates with sensitivity to GSK3368715 in cell lines. These data provide rationale to explore MTAP status as a biomarker strategy for patient selection."

Biomarker • Journal

M-TAP Dance: Targeting PRMT1 and PRMT5 Family Members to Push Cancer Cells Over the Edge. (PubMed, Cancer Cell) - "In this issue of Cancer Cell, Fedoriw and colleagues characterize a potent reversible inhibitor of type I PRMTs, GSK3368715, with anti-proliferative effects on numerous cancer types. Using a combination of GSK3368715 with PRMT5 inhibitors, the authors show that a threshold of overall arginine methylation reduction needs to be achieved for synergistic anti-tumor activity."

Journal

A patent review of arginine methyltransferase inhibitors (2010-2018). (PubMed, Expert Opin Ther Pat) - "So far, three PRMT inhibitors have entered clinical trials, including PRMT5 inhibitor GSK3326595 and JNJ-64619178 as well as PRMT1 inhibitor GSK3368715. PRMT inhibitors with novel mechanism of action and good drug-like properties may shed new light on drug research and development progress."

Biomarker • Journal • Review

Epizyme earns $8 million milestone payment from GlaxoSmithKline for initiation of clinical development for first-in-class PRMT1 inhibitor (GlobeNewswire) - "Epizyme, Inc. (Nasdaq: EPZM), a clinical-stage company developing novel epigenetic therapies, today announced it has earned an $8 million milestone payment from GlaxoSmithKline (GSK). The milestone payment follows GSK’s initiation of patient dosing in a Phase 1 clinical trial of GSK3368715, a first-in-class protein arginine methyltransferase1 (PRMT1) inhibitor discovered by Epizyme and licensed to GSK. PRMT1 has been implicated in a number of human cancers."

Financing