P1, N=27, Recruiting, Servier Bio-Innovation LLC | Not yet recruiting --> Recruiting

The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ'9567 (21), a potent inhibitor in vitro with excellent preclinical pharmacokinetic properties. This tool showed a selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro and in vivo, providing further evidence to support the utility of MAT2a inhibitors as potential anticancer therapies for MTAP-deficient tumors.

X-ray co-crystal structure revealed that compound 7 fully occupies the allosteric pocket of MAT2A as a single molecule mimicking MAT2B. By introducing additional backbone interactions and rigidifying the requisite linker extensions, we generated compound 8, which exhibited single digit nanomolar enzymatic and sub-micromolar cellular inhibitory potency for MAT2A.

Owing to the MAT2A degradation merits, H3 at a dosage of 10 mg/kg induced 31% tumor regression in xenograft colon tumor models. The significantly boosted antitumor potency can potentially alleviate the toxicity of high-dose MAT2A inhibitors to normal cells and tissues, especially to the liver.

P1, N=27, Not yet recruiting, Servier Bio-Innovation LLC

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.

P1, N=130, Recruiting, IDEAYA Biosciences | N=382 --> 130

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.

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.

Taken together, our study displayed that miR-26b-5p/MAT2A triggers ferroptosis in OS cells by increasing intracellular ferrous iron levels and inhibiting the STAT3/SLC7A11 axis. Our results reveal a MAT2A-mediated ferroptosis defense mechanism used by OS cells and propose a potential ferroptosis-inducing strategy for the treatment of OS patients.

P1, N=123, Terminated, Institut de Recherches Internationales Servier | Completed --> Terminated; Strategic reasons

The present study demonstrated the translocation of MAT2A and its prognostic relevance in female LIHC patients. Our findings suggest the potential of estrogen in SP1 regulation and localization of MAT2A, as therapeutic modalities against in female LIHC patients.

P1, N=123, Completed, Institut de Recherches Internationales Servier | Active, not recruiting --> Completed

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.

We noted synergistic antiproliferative effects when the potent and selective MAT2A inhibitor IDE397 was combined with any of multiple MTA-cooperative PRMT5 inhibitors in MTAPdel cell lines that exhibit sensitivity to each single agent...The potentiation of the antitumor response with the combination did not occur in the MTAPWT setting. Thus, combined inhibition of MAT2A and PRMT5 potentially offers a compelling dual synthetic lethal opportunity to address unmet need for the many patients afflicted with MTAPdel cancers.

Synergy between IDE397 and pemetrexed was of particular interest given mechanistic convergence of the methionine salvage and folate cycle pathways on nucleotide synthesis in the context of MTAP-/-. Collectively, these observations indicate that MAT2A inhibition can generate cell states in MTAP-/- tumor cells that are selectively vulnerable to approved chemotherapies and targeted therapies. These synergistic relationships may provide a predictive biomarker strategy for multiple IDE397 synthetic lethal combination therapies.

OGT and FLAD1 showed significant prognostic factors of disease progression, even after adjustment for confounding clinicopathological parameters in non-metastatic prostate cancer.

Furthermore, the methyltransferase domain of METTL16 methylated U6 snRNA with an apparent dissociation constant of 736 μM and a k of 0.42 min, suggesting that the missing vertebrate conserved regions weaken the ternary complex but do not induce any rate-limiting conformational rearrangements of the U6 snRNA. This study helps us to better understand the catalytic activity of METTL16 in the context of its biological functions.

P1/2, N=0, Withdrawn, Institut de Recherches Internationales Servier | N=105 --> 0 | Initiation date: Aug 2022 --> May 2025 | Not yet recruiting --> Withdrawn | Trial primary completion date: Dec 2025 --> Jun 2026

These findings establish a novel characterization of the signaling transduction and the metabolic consequences of dietary methionine restriction in malignant liver tissue of mice. mTORC1, c-Myc, SIRT4 and ADP ribosylation site of MAT2A are promising clinical and therapeutic targets for the HCC treatment.

As a follow-up, we also performed a drug screen using 214 compounds to identify drugs that interact with MR, showing that vinca-alkaloids, including vincristine, strongly synergize...In summary, we found that MLLr leukemic cells are selectively vulnerable to perturbations of the methionine cycle due to their increased need for SAM to maintain hypermethylation and aberrant gene activation. Limiting methionine and/or SAM availability provides an attractive adjuvant therapy potentiating the effects of current or novel (targeted) therapies for MLLr leukemia.

nsp ≥ 0.05, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are representative of at least three independent experiments, are shown as mean ± SD, and are compared among multiple groups by one-way analysis of variance (ANOVA).

Agios and Ideaya in particular have capitalised on an allosteric binding mode first published by Pfizer in at least two of the filings during this time period leading to potent, selective inhibitors and have advanced MAT2a inhibitors to phase I clinical studies to explore their benefit to patients suffering with MTAP-deficient solid tumours or lymphoma. Whilst the other patent disclosures during this time frame have not led to disclosed candidates, the trials initiated by Agios and Ideaya studies will clearly inform on the potential for such inhibitors as viable therapeutic agents either as single agent or in combination.

Targeted inhibition of the upregulated oncogene in the KDM2A-depleted cells led to a synergistic suppressive effect on the malignant phenotype of ESCC cells. Our results revealed the dual role of KDM2A in ESCC cells, which may have therapeutic implications.

In summary, MAT2A inhibition reduced MM cell proliferation and survival by inhibiting m-TOR mediated protein synthesis. Our findings suggest that the MAT2A inhibitor FIDAS-5 could be a novel compound in bortezomibbased combination therapies for MM.

P1, N=123, Active, not recruiting, Institut de Recherches Internationales Servier | Recruiting --> Active, not recruiting

Furthermore, a perspective on the use of MAT2A inhibitors for the treatment of cancer is also discussed. We hope to provide guidance for future drug design and optimization via analysis of the binding modes of known MAT2A inhibitors.

Primary endpoints include safety and tolerability, RP2D determination, investigator-assessed tumor response by RECIST v1.1. Enrollment in the monotherapy dose escalation is ongoing with clearance of the first 5 dose levels without DLT.

Our results show that four ICC stemness-associated genes could serve as novel biomarkers in predicting ICC patient's response to adjuvant TACE and their pro-stemness ability may be attributed to the activation of the methionine cycle.

P1, N=382, Recruiting, IDEAYA Biosciences | N=40 --> 382 | Trial completion date: Dec 2024 --> Jun 2024 | Trial primary completion date: Dec 2022 --> Dec 2023

MALAT1 ablation was found to reduce methylation in MAT2A hairpin1 and increase MAT2A protein levels. Our results suggest a MALAT1-METTL16-MAT2A interactive axis which may be targeted for treatments of sepsis.

Together, folate promotes the integration of methionine and one-carbon metabolism, contributing to HCC development via hijacking MATIIα metabolic pathway. This study provides insight into folate-promoted cancer development, strongly recommending the tailor-made folate supplement guideline for both sub-healthy populations and patients with cancer expressing high level of MATIIα expression.

Finally, the global histone methylation (H3K4me3, H3K9me2, H3K27me3, H3K36me3) was reduced under methionine deficiency conditions, while H3K9me2 and H3K36me3 were decreased specially via PF9366. Methionine deficiency or MAT2A inhibition may modulate genes expression associated with apoptosis, DNA repair and TNF signaling pathways by regulating histone methylation, thus promoting the sensitivity of lung cancer cells to cisplatin.

Moreover, methionine-restricted diets extended survival in multiple models of DMG in vivo. Collectively, our results suggest that MAT2A presents an exploitable therapeutic vulnerability in H3K27M gliomas.

Furthermore, the clinical analysis indicates that the MAT2A protein level is positively associated with the PDCD6 level, and the high level of PDCD6 significantly correlates with poor prognosis and advanced stages of cervical cancer patients. We conclude that MAT2A facilitates PDCD6 methylation to promote cervical cancer growth under glucose deprivation, suggesting the regulatory role of MAT2A in cellular response to nutrient stress and cervical cancer progression.

SAM administration antagonizes pathological conditions, including galactosamine, acetaminophen, and ethanol intoxications, characterized by decreased intracellular SAM. Positive therapeutic effects of SAM/vitamin E or SAM/ursodeoxycholic acid in animal models with NAFLD and intrahepatic cholestasis were not confirmed in humans. In in vitro experiments, SAM and betaine potentiate PegIFN-alpha-2a/2b plus ribavirin antiviral effects...SAM plus Decitabine arrest cancer growth and potentiate doxorubicin effects on breast, head, and neck cancers. Furthermore, SAM enhances the antitumor effect of gemcitabine against pancreatic cancer cells, inhibits growth of human prostate cancer PC-3, colorectal cancer, and osteosarcoma LM-7 and MG-63 cell lines; increases genomic stability of SW480 cells. SAM reduces colorectal cancer progression and inhibits the proliferation of preneoplastic rat liver cells in vivo. The discrepancy between positive results of SAM treatment of experimental tumors and modest effects against human disease may depend on more advanced human disease stage at moment of diagnosis.

Collectively, these results established a link between methionine cycle activity and ferroptosis vulnerability in gastric cancer.