S095033 / Servier - LARVOL DELTA

Resetting the Aberrant Methylation Landscape and DNA Damage Response in Multiple Myeloma Through MAT2A Targeting Reveals Novel Combination Strategies. (IMS 2026) - " MAT2A knockdown (KD) in OPM2 and AMO-1 cell lines was achieved using doxycycline inducible lentiviral shRNA vectors targeting MAT2A. In conclusion, targeting MAT2A in MM cells reverts aberrant methylation and impairs pro-tumoral signalling offering promising avenues for more effective combination therapies."

Hematological Malignancies • Multiple Myeloma • ANXA5 • KRAS • MAT2A

Integrating proteomics and metabolomics to reveal MAT2A for metabolic reprogramming in non-small cell lung cancer cells. (PubMed, iScience) - "In fatty acid biosynthesis, MAT2A regulates FASN and SCD; exogenous palmitic acid reverses AG-270-induced growth inhibition, supporting combination with the FASN inhibitor TVB-2640. In the transsulfuration pathway, MAT2A transcriptionally regulates CBS and shows synergy with inhibitors of PHGDH (producing serine for cysteine biosynthesis) and SLC7A11 (mediating cysteine uptake). Collectively, our findings establish MAT2A as a central metabolic regulator in NSCLC and propose rational combination strategies."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HIF1A • MAT2A • PHGDH • SLC2A1 • SLC7A11

Multi-Omics Analysis Reveals the Role of MAT2A in Metabolic Reprogramming of Non-Small Cell Lung Cancer (IASLC-WCLC 2026) - "Conclusions : Our multi-omics analysis demonstrates MAT2A's role in regulating lipid metabolism, glycolysis, and transport pathways in NSCLC, and we demonstrate a highly synergistic combination strategy involving AG-270 and the LXR agonist LXR-623. $$graphic_E01BD86E-ABCA-4643-9049-8BDADE0E99AE$$ $$graphic_4FF732BA-491C-4E38-8736-87AD584B0CA0$$"

Lung Cancer • Metabolic Disorders • Non Small Cell Lung Cancer • Oncology • Solid Tumor • FASN • HIF1A • MAT2A • PHGDH • SLC2A1 • SLC7A11

Proteome-wide mapping of S-adenosylmethionine interactions reveals novel regulatory targets (SSIEM 2026) - "Lysates were treated with 0.01-1 mM SAM, S-adenosylhomocysteine (SAH), methylthioadenosine (MTA), or DMSO, together with two structurally distinct methionine adenosyltransferase 2A inhibitors (AG-270 and IDE397) as binding selectivity controls. This study provides a proteome-wide view of SAM-binding proteins, offering new insights into its role as a global allosteric regulator. Ongoing work will determine how SAM binding influences the function of these newly identified targets. Overall, our findings expand the current understanding of SAM-mediated regulation in human cells."

Metabolic Disorders • MAT2A • MTHFR

Targeting MAT2A-mediated metabolic pathways: A novel strategy for non-small cell lung cancer therapy. (ASCO 2026) - " We systematically characterized the metabolic reprogramming of MAT2A rewiring in NSCLC cell lines treated with siRNA targeting MAT2A or inhibitor AG-270 using proteomics and metabolomics, supplemented by targeted metabolomics, RT qPCR, and ATAC seq, in order to characterize MAT2A-rewired metabolic reprogramming and identify potential combination strategies... Overall, our research findings confirm that MAT2A is a critical regulatory factor in NSCLC metabolism and propose a reasonable combination strategy to enhance the efficacy of MAT2A inhibitors."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • FASN • HIF1A • MAT2A • PHGDH • SLC2A1 • SLC7A11

Therapeutic vulnerabilities exposed by the 9p21 loss identified through multiparametric drug screening inform rational combination strategies. (PubMed, NPJ Precis Oncol) - "We identified cytarabine and methotrexate as significantly more effective in the 9p21 compromised BLCA cells. Analysis of morphological alterations further supported a genotype-specific activity of nucleoside analogs, nominating gemcitabine as a drug with greater efficacy in this context...Synergy between cytarabine and inhibitors of PRMT5 (MRTX1719) and MAT2A (AG-270) was mediated by a differential activation of DNA damage and replication stress markers, suggesting an exploitable vulnerability. In fact, rational drug combinations with ATR/CHK1 pathway inhibitors increased efficacy while maintaining 9p21-specificity. Finally, we confirmed the effectiveness of these combinations in cell models of pancreatic adenocarcinoma and pleural mesothelioma, two tumor types with high prevalence of MTAP loss and, most notably, in bladder cancer patient-derived organoids, underscoring the strong translational potential of our findings."

Journal • Bladder Cancer • Genito-urinary Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pleural Mesothelioma • Solid Tumor • CDKN2A • CDKN2B • MAT2A • MTAP

The Combination of Methionine Adenosyltransferase 2A (MAT2A) Inhibitor AG-270 and Recombinant Methioninase Is Not Cancer-selective in a Co-culture Model of Colon Cancer Cells and Normal Fibroblasts. (PubMed, Cancer Diagn Progn) - "In contrast, rMETase combined with numerous first-line chemotherapeutic drugs acted selectively and synergistically against cancer cells while sparing normal cells, including co-culture models. The present results suggest that AG-270 may have limited potential as an anticancer agent."

Journal • CNS Disorders • Colon Cancer • Colorectal Cancer • Oncology • Psychiatry • Solid Tumor • MAT2A

Lack of Cancer Specificity of Methionine Adenosyltransferase 2A (MAT2A) Inhibitor AG-270 in Combination With Recombinant Methioninase In Vitro. (PubMed, Anticancer Res) - "AG-270 showed lack of cancer specificity in combination with rMETase when tested on both cancer and normal cells. The present results contrast with numerous chemotherapy agents, which in combination with rMETase are synergistic on cancer cells but not on normal cells. The present findings suggest that MAT2A inhibition affects crucial metabolic pathways in normal as well as cancer cell types and thus AG-270 may not be suitable as a cancer-specific therapeutic strategy."

Journal • Preclinical • CNS Disorders • Colon Cancer • Colorectal Cancer • Oncology • Psychiatry • Solid Tumor • MAT2A

Design, Synthesis, and Preclinical Evaluation of a PET Tracer Targeting Methionine Adenosyltransferase 2A. (PubMed, J Med Chem) - "This study developed two novel MAT2A-targeted PET tracers: the 18F-labeled [18F]1d, derived from AZ-28, demonstrates rapid tumor uptake (equilibrium ∼20 min), high tumor-to-muscle ratio, and specific MAT2A binding in H1975 xenografts, though it shows some bone uptake due to defluorination; the 68Ga-labeled [68Ga]1s, based on AG-270, retains high MAT2A affinity (IC50 = 6.23 nM) and exhibits superior pharmacokinetics─low liver uptake, renal clearance, and high cellular internalization (80%)...Molecular docking confirms key interactions with the MAT2A allosteric site. Both tracers provide promising tools for solid tumor diagnosis, treatment monitoring, and precision oncology."

Journal • Preclinical • Oncology • Solid Tumor • MAT2A

Single Cell Multi-Omic Analysis of Neoplastic Plasma Cells across the Disease Spectrum Identifies Novel Pathobiologic Mediators and Potential Therapeutic Targets in Multiple Myeloma (MM) (ASH 2023) - "Notably, MAD2L1 inhibition with M2I1, and MAT2A targeting with the allosteric inhibitor AG-270, both produced a dose- and time-dependent inhibition in cell proliferation and reduction in myeloma cell line viability... Our combined single-cell transcriptomics and VDJ sequencing allowed a greater understanding of heterogeneity among neoplastic PCs compared to each patient's own polyclonal PCs. These analyses can identify putative novel mediators of disease pathobiology that impact prognosis, and that can serve as potential new therapeutic targets using either novel agents, or drug repurposed from other therapeutic areas, setting the stage for their translation to the clinic."

IO biomarker • Omic analysis • Hematological Malignancies • Monoclonal Gammopathy • Multiple Myeloma • Oncology • Plasmacytoma • CD27 • DKK1 • HGF • LDHA • MAD2L1 • MAT2A

TARGETING MAT2A ALTERS THE METHYLATION LANDSCAPE AND DNA DAMAGE RESPONSE IN MULTIPLE MYELOMA, REVEALING NOVEL COMBINATION STRATEGIES. (EHA 2025) - "Moreover, FIDAS-5 was able to improve bortezomib-based treatment...The impact of MAT2A depletion on DNA methylation and histone methylation was evaluated using Enzymatic Methyl sequencing (EM-seq) and western blot, while the impact on the transcriptome was determined by RNA sequencing (RNA-seq).Doxycycline inducible stable KD of MAT2A in MM cells using shRNA confirmed the tumor promoting role of MAT2A... In conclusion, our research highlights that targeting MAT2A in MM cells reverts aberrant methylation processes and impairs several pro-tumoral signalling pathways, offering promising avenues for developing more effective combination treatments for MM."

Hematological Malignancies • Multiple Myeloma • Oncology • ANXA5 • MAT2A

Structure-Based Discovery of a Series of Novel MAT2a Inhibitors. (PubMed, ACS Med Chem Lett) - "Guided by the costructure of AZ-28 in complex with the MAT2a dimer, compound 9 was synthesized, demonstrating potent MAT2a inhibition (IC50 = 20 nM) and significantly enhanced antiproliferative activity (IC50 = 10 nM against HAP1MTAP-/- cells). Moreover, compound 9 exhibited improved selectivity compared to both AZ-28 and AG-270."

Journal • Oncology • MAT2A • MTAP

MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial (Nat Commun, Nature) - P1 | N=123 | NCT03435250 | Sponsor: Institut de Recherches Internationales Servier | "Forty patients were treated with AG-270/S095033. Plasma concentrations of AG-270/S095033 increased with dose. Maximal reductions in plasma SAM concentrations ranged from 54% to 70%. Analysis of paired tumor biopsies showed decreases in levels of symmetrically di-methylated arginine (SDMA) residues. Reversible increases in liver function tests, thrombocytopenia, anemia and fatigue were common treatment-related toxicities. Two partial responses were observed; five additional patients achieved radiographically confirmed stable disease for ≥16 weeks. AG-270/S095033 has a manageable safety profile."

P1 data • Cholangiocarcinoma • Mesothelioma • Non Small Cell Lung Cancer • Pancreatic Cancer

MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial (Nat Commun, Nature) - P1 | N=123 | NCT03435250 | Sponsor: Institut de Recherches Internationales Servier | "Forty patients were treated with AG-270/S095033. Plasma concentrations of AG-270/S095033 increased with dose. Maximal reductions in plasma SAM concentrations ranged from 54% to 70%. Analysis of paired tumor biopsies showed decreases in levels of symmetrically di-methylated arginine (SDMA) residues. Reversible increases in liver function tests, thrombocytopenia, anemia and fatigue were common treatment-related toxicities. Two partial responses were observed; five additional patients achieved radiographically confirmed stable disease for ≥16 weeks. AG-270/S095033 has a manageable safety profile."

P1 data • Cholangiocarcinoma • Mesothelioma • Non Small Cell Lung Cancer • Pancreatic Cancer

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

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. (PubMed, MedComm (2020)) - "Different from AG-270, SCR-7952 exhibited little influence on metabolic enzymes and did not increase the plasma levels of bilirubin. 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."

Combination therapy • Journal • Oncology • FANCA • MAT2A • MTAP

The combination of methionine adenosyltransferase 2A inhibitor and methyltransferase like 3 inhibitor promotes apoptosis of non-small cell lung cancer cells and produces synergistic anti-tumor activity. (PubMed, Biochem Biophys Res Commun) - "Therefore, in order to expand the applicability of inhibitors, improve anti-tumor effects and reduce toxicity, the combinational effect of MAT2A inhibitor AG-270 and METTL3 inhibitor STM2457 was evaluated in NSCLC...More importantly, the combination also exerted synergistic effects in vivo. In summary, the combination of MAT2A inhibitor and METTL3 inhibitor showed synergistic effects both in vivo and in vitro, which laid a theoretical foundation for expanding the clinical application research of the two types of drugs."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MAT2A • METTL3 • MTAP

Discovery of Potent and Oral Bioavailable MAT2A Inhibitors for the Treatment of MTAP-Deleted Tumors. (PubMed, ACS Med Chem Lett) - "The selected compound 30 exhibited high potency for MAT2A inhibition and a favorable pharmacokinetic profile. Furthermore, in an HCT-116 MTAP-deleted xenograft model, compound 30 showed better in vivo potency than current clinical compound AG-270."

Journal • Oncology • MAT2A • MTAP

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

Study of AG-270 in Participants With Advanced Solid Tumors or Lymphoma With MTAP Loss (clinicaltrials.gov) - P1 | N=123 | Terminated | Sponsor: Institut de Recherches Internationales Servier | Completed ➔ Terminated; Strategic reasons

Metastases • Trial termination • Gastrointestinal Cancer • Hematological Malignancies • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CDKN2A • MTAP

Study of AG-270 in Participants With Advanced Solid Tumors or Lymphoma With MTAP Loss (clinicaltrials.gov) - P1 | N=123 | Completed | Sponsor: Institut de Recherches Internationales Servier | Active, not recruiting ➔ Completed

Trial completion • Gastrointestinal Cancer • Hematological Malignancies • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CDKN2A • MTAP

Discovery of novel, potent and orally available MAT2A inhibitors (AACR 2023) - "We describe here potent and orally bioavailable MAT2A inhibitors (“Euregen MAT2Ais”) with superior potency and selectivity compared to AG-270...Furthermore, Euregen MAT2Ais revealed excellent oral bioavailability and PK properties in pre-clinical species. We are optimizing multiple MAT2A inhibitors that exhibit activity across a wide range of cancers with MTAP-deletion."

Oncology • CDKN2A • MAT2A • MTAP

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

Design and Structural Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High In Vivo Potency and Oral Bioavailability. (PubMed, J Med Chem) - "More importantly, introducing an amide motif (28) to the core structure raised the plasma drug exposure from 11 718 to 41 192 ng·h·mL. 28 displayed a significantly better in vivo potency than AG-270, which is being evaluated in clinical trails, and induced -52% tumor regression in a xenograft MTAP-depleted colon tumor model."

Journal • Preclinical • Colon Cancer • Gastrointestinal Cancer • Oncology • MAT2A • MTAP

A phase 1 trial of AG-270 in patients with advanced solid tumors or lymphoma with homozygous MTAP deletion (AACR-NCI-EORTC 2019) - P1; "Conclusion AG-270 causes reductions in plasma [SAM] and in tumor SDMA levels at well-tolerated doses. This trial will next evaluate the combination of AG-270 with taxane-based chemotherapy, given preclinical data demonstrating enhanced antitumor activity with AG-270 and taxanes in MTAP-deleted cancer models."

Clinical • P1 data