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AG 270 (AG-270; AG270) is a novel, first-in-class, reversible, allosteric, noncompetitive and orally bioactive MAT2A inhibitor( IC50 =14 nM) with anticancer activity. It substantially reduce SAM levels in cancer cells and selectively block proliferation of MTAP-null cells both in tissue culture and xenograft tumors. The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was recently implicated as a synthetic lethal target in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene
| ln Vitro |
In an in vitro HCT116 MTAP syngeneic cell model, AG-270 demonstrates selective antiproliferative activity that effectively lowers intracellular SAM levels and MTAP ineffectiveness [1]. In HCT116 MTAP-null cell SAM, AG-270 has an IC50 of 20 nM after 72 hours [1]. The production of the ubiquitous methyl donor S-adenosylmethionine (SAM) is carried out by MAT2A, an essential enzyme in the methionine salvage pathway [2].
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| ln Vivo |
In a variety of species, including humans, mice, rats, dogs, and monkeys, AG-270 demonstrates exceptional microsomal, hepatocyte, and in vivo metabolic stability. With regard to mice, rats, monkeys, and dogs, the corresponding T1/2 values for AG-270 are 5.9 h, 4.2 h, 4.8 h, and 21.3 h [1]. AG-270 (200 mg/kg, PO, once daily for 38 days) was well tolerated, with a mean weight loss of less than 5%, and it reduced tumor SAM levels and tumor growth in KP4 MTAP-null xenografts in a dose-dependent manner[1]. Benefits of combination therapy have been observed in PDX models of cancer. AG-270 produced additive synergistic antitumor activity in combination with taxanes and gemcitabine, and docetaxel produced complete tumor regression in 50% of selected models; in patients with tumors originating from non-small cell lung cancer, pancreas cancer, and esophageal cancer [2].
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| Animal Protocol |
Animal/Disease Models: Pancreatic KP4 MTAP-null xenograft mouse model [1].
Doses: 10-200 mg/kg. Route of Administration: po (po (oral gavage)) one time/day for 38 days. Experimental Results: Resulting in a dose-dependent reduction in tumor SAM levels and tumor growth in KP4 MTAP-null xenografts (TGI = 36% (10 mg/kg), 48% (30 mg/kg), 66% (100 mg/kg) ), 67% (200 mg/kg). |
| References | |
| Additional Infomation |
MAT2A Inhibitor AG-270 is an orally available small molecule inhibitor of methionine adenosyltransferase II alpha (MAT2A) with potential antineoplastic activity. Upon administration, AG-270 inhibits the activity of MAT2A, a metabolic enzyme responsible for the production of S-Adenosyl-L-methionine (SAM), a primary donor of methyl groups in cellular transmethylation reactions that regulate gene expression, cell growth, and differentiation. MAT2A activity is selectively essential in cancer cells deficient in methylthioadenosine phosphorylase (MTAP), a critical enzyme in the methionine salvage pathway, that is deleted in some human cancers. Inhibition of MAT2A may potentially inhibit tumor cell growth in MTAP-deleted cancers that rely heavily on SAM synthesis.
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| Molecular Formula |
C30H31N5O2
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|---|---|
| Molecular Weight |
493.5994
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| Exact Mass |
489.216
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| CAS # |
2201056-66-6
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| Related CAS # |
2201056-66-6 (free);2761546-65-8 (sodium);
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| PubChem CID |
134307820
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| Appearance |
White to off-white solid powder
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| LogP |
5.6
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
37
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| Complexity |
997
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1C(C2C([H])=C([H])C(=C([H])C=2[H])OC([H])([H])[H])=C(N([H])C2=C([H])C([H])=C([H])C([H])=N2)N([H])C2([H])C([H])(C3=C([H])C([H])([H])C([H])([H])C([H])([H])C3([H])[H])C([H])(C3C([H])=C([H])C([H])=C([H])C=3[H])N([H])N21
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| InChi Key |
LSOYYWKBUKXUHQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C30H27N5O2/c1-37-23-17-15-21(16-18-23)26-28(32-24-14-8-9-19-31-24)33-29-25(20-10-4-2-5-11-20)27(34-35(29)30(26)36)22-12-6-3-7-13-22/h3,6-10,12-19,34H,2,4-5,11H2,1H3,(H,31,32)
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| Chemical Name |
3-(cyclohexen-1-yl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2-ylamino)-1H-pyrazolo[1,5-a]pyrimidin-7-one
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| Synonyms |
AG-270AG 270AG270
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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 |
| 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 : ~4 mg/mL (~8.17 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 4.75 mg/mL (9.70 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 47.5 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: ≥ 4.75 mg/mL (9.70 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 47.5 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0259 mL | 10.1297 mL | 20.2593 mL | |
| 5 mM | 0.4052 mL | 2.0259 mL | 4.0519 mL | |
| 10 mM | 0.2026 mL | 1.0130 mL | 2.0259 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.
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