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MAT2A inhibitor 2 HCl salt is a novel and potent inhibitor of methionine adenosyltransferase 2A (MAT2A) with potential anticancer activity. MAT2a is a methionine adenosyltransferase that synthesizes the essential metabolite S-adenosylmethionine (SAM) from methionine and ATP.
| Targets |
MAT2A (methionine adenosyltransferase II alpha). [1]
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| ln Vitro |
AG-270 suppressed osteoclast formation in a dose-dependent manner at concentrations of 1 to 2.5 μmol/L, as determined by TRAP staining. No significant cell toxicity was observed in bone marrow-derived macrophages (BMMs) at concentrations up to 2.5 μmol/L (CCK8 assay). [1]
- AG-270 (2.5 μmol/L) inhibited osteoclast formation mainly at the early stage of osteoclast induction. [1] - AG-270 inhibited podosome formation in mature osteoclasts in a concentration-dependent manner, as shown by F-actin staining; the number and volume of podosomes (podosome clusters, actin rings, and podosome belts) were significantly decreased compared to control. [1] - AG-270 reduced the bone resorption area of mature osteoclasts on hydroxyapatite-coated plates, measured by pit formation assay. [1] - AG-270 suppressed mRNA expression levels of osteoclast marker genes (NFATc1, c-FOS, TRAP, CTSK, MMP9) in a concentration-dependent manner (qPCR). Western blot confirmed inhibition of these marker proteins. [1] - AG-270 reduced RANKL-induced cellular reactive oxygen species (ROS) level in BMMs in a concentration-dependent manner (DCFH-DA fluorescence assay). [1] - AG-270 activated Nrf2 signaling (increased Nrf2, HO1, NQO1 protein levels) and suppressed NF-κB pathway (decreased phosphorylation of p65 and IκBα, decreased IκBα degradation) and MAPK pathway (decreased p-p38 and p-JNK) as shown by western blot. [1] |
| ln Vivo |
In a murine ovariectomy (OVX)-induced osteoporosis model (12-week-old female C57BL/6 mice), oral administration of AG-270 at low dose (30 mg/kg) and high dose (100 mg/kg) daily for 6 weeks significantly attenuated OVX-induced bone loss. μ-CT analysis showed improved bone volume/tissue volume (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th), and reduced trabecular space (Tb.Sp) compared to OVX+VEH group. The higher dose (100 mg/kg) showed better improvement. [1]
- TRAP staining of bone tissue slices revealed that AG-270 (30 or 100 mg/kg) reduced the enhanced osteoclast formation and osteoclast surface/bone surface ratio (Oc.S/BS) induced by OVX. [1] - Sham-operated mice treated with AG-270 (100 mg/kg) showed no significant difference in bone parameters compared to sham+VEH group. [1] |
| Cell Assay |
For in vitro osteoclastogenesis assay, BMMs isolated from 8-week-old C57BL/6 mice were cultured in α-MEM medium containing 30 ng/ml M-CSF and 75 ng/ml RANKL for 5 days to induce osteoclast differentiation. AG-270 was added at various concentrations (1, 1.5, 2, 2.5 μmol/L) or at different time points (days 0-5) to determine the stage of inhibition. TRAP staining was performed, and TRAP-positive multinucleated cells (≥3 nuclei) were counted as osteoclasts. [1]
- Cell proliferation assay (CCK8): BMMs were seeded in 96-well plates (5×10³ cells/well) in complete medium with 30 ng/ml M-CSF for 24 h, then treated with various concentrations of AG-270 for 1, 3, and 5 days. CCK8 assay was performed according to manufacturer's instructions. [1] - F-actin staining and pit formation assay: BMMs were cultured on 0.2% collagen gel-coated 6-well plates with M-CSF and RANKL for 6 days, then digested with collagenase and seeded onto hydroxyapatite-coated Osteo Assay strip well plates. Mature osteoclasts were treated with AG-270 (0, 1, 2, 2.5 μmol/L) for 2 days. Cells were fixed with 4% paraformaldehyde for F-actin staining (phalloidin-rhodamine), or lysed and washed for pit formation assay (resorption area analyzed by ImageJ). [1] - RNA extraction and qPCR: Total RNA was extracted using TRIzol, reverse transcribed to cDNA, and qPCR performed using SYBR Green. Relative mRNA levels of MMP9, NFATc1, CTSK, TRAP, and β-Actin (reference) were calculated by 2-ΔΔCT method. BMMs were treated with AG-270 (0, 1, 1.5, 2, 2.5 μmol/L) for 2 days, or with 2.5 μmol/L AG-270 at different days. [1] - Western blot: Total protein extracted with RIPA buffer containing phosphatase and protease inhibitors, separated by 10% SDS-PAGE, transferred to PVDF membranes, blocked with 5% BSA, incubated with primary antibodies overnight at 4°C, then HRP-conjugated secondary antibodies, and detected with ECL. [1] - ROS measurement: BMMs were seeded in 48-well plates (4×10⁴ cells/well), treated with M-CSF, RANKL, and various concentrations of AG-270 for 48 h, then incubated with diluted DCFH-DA (10 mm) for 20 min at 37°C in the dark, and fluorescence images captured. [1] |
| Animal Protocol |
Murine model of ovariectomy (OVX)-induced bone loss: Twelve-week-old female C57BL/6 mice were randomly divided into five groups (n=8 each): SHAM+VEH, SHAM+AG-270 (100 mg/kg), OVX+VEH, OVX+AG-270 low dose (30 mg/kg), OVX+AG-270 high dose (100 mg/kg). Mice were anesthetized with 1% pentobarbital in normal saline; bilateral ovaries were exposed via a dorsal approach and removed (OVX) or only exposed (sham). Three days after surgery, mice were treated daily with oral (PO) AG-270 or vehicle (6.7% w/w HPMCAS-MF, 1% w/w PVP K30, 2% w/w TPGS, 0.1% Simethicone) for 6 weeks. Then mice were sacrificed, and serum, femurs, and tibias were collected. [1]
- Microcomputed tomography (μ-CT) scanning: Left femurs were fixed with 4% paraformaldehyde and scanned (100 kV, 98 μA, 10 μm voxel size). 3D images and trabecular parameters (BV/TV, Tb.N, Tb.Th, Tb.Sp) were analyzed using μ-CT system software. [1] - Histomorphometric analysis: Right femurs were fixed, decalcified with 10% EDTA, and TRAP staining was performed on bone tissue slices. Parameters including number of osteoclasts per bone perimeter (N.Oc/B.Pm) and osteoclast surface per bone surface (Oc.S/Bs) were analyzed. [1] |
| References | |
| Additional Infomation |
AG-270 is described as an oral, first-in-class MAT2A inhibitor. It was used to demonstrate that inhibition of MAT2A suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss, suggesting MAT2A as a potential therapeutic target for osteoporosis attributed to osteoclast dysfunction. [1]
- The study used AG-270 at concentrations of 1-2.5 μmol/L in vitro, and at oral doses of 30 mg/kg and 100 mg/kg daily in vivo. [1] - AG-270 treatment in sham-operated mice did not alter bone parameters, indicating no adverse effects on normal bone homeostasis. [1] |
| Molecular Formula |
C18H24CLN3O3
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|---|---|
| Molecular Weight |
365.858
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| Exact Mass |
365.151
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| CAS # |
13299-99-5
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| Related CAS # |
13299-99-5 (HCl);13299-98-4;
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| PubChem CID |
202785
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| Appearance |
White to off-white solid powder
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| Vapour Pressure |
1.14E-09mmHg at 25°C
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| LogP |
2.299
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
25
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| Complexity |
512
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
REOUTEBTFSILJY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H23N3O3.ClH/c1-14-12-17(15-4-3-5-16(13-15)23-2)19-21(18(14)22)7-6-20-8-10-24-11-9-20/h3-5,12-13H,6-11H2,1-2H31H
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| Chemical Name |
6-(m-Methoxyphenyl)-4-methyl-2-(2-morpholinoethyl)-3(2H)-pyridazinone hydrochloride
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~75 mg/mL (~205.00 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.83 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.83 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.83 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7333 mL | 13.6664 mL | 27.3329 mL | |
| 5 mM | 0.5467 mL | 2.7333 mL | 5.4666 mL | |
| 10 mM | 0.2733 mL | 1.3666 mL | 2.7333 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05312372 | Withdrawn | Drug: Combination (S095033 + paclitaxel) |
Esophageal Squamous Cell Carcinoma | Institut de Recherches Internationales Servier |
May 2025 | Phase 1 Phase 2 |
| NCT04794699 | Recruiting | Drug: IDE397 Drug: Docetaxel |
Solid Tumor | IDEAYA Biosciences | April 14, 2021 | Phase 1 |
| NCT06188702 | Recruiting | Drug: S095035 | MTAP-deleted Solid Tumors | Servier Bio-Innovation LLC | April 29, 2024 | Phase 1 |
| NCT03435250 | Terminated | Drug: AG-270 Drug: docetaxel |
Advanced Solid Tumors Lymphoma |
Institut de Recherches Internationales Servier |
March 4, 2018 | Phase 1 |
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