AG-270是一种强效、口服活性的甲硫氨酸腺苷转移酶2A（MAT2A）变构抑制剂，其IC50为14nM。
Cas No.:2201056-66-6
Sample solution is provided at 25 µL, 10mM.
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AG-270 is a potent, orally active, allosteric inhibitor of methionine adenosyltransferase 2A (MAT2A) with an IC50 of 14nM [1,2]. MAT2A is a cytoplasmic enzyme. The enzyme has been identified as a synthetic lethal target in cancers that the methylthioadenosine phosphorylase (MTAP) gene was deleted [3]. AG-270 can induce synthetic lethality and prevent proliferation of MTAP-deleted cancer cells. AG-270 is also applied in the fields of immune system diseases, hematologic and lymphatic system diseases.
In vitro, AG-270 not only reduces intracellular S-adenosylmethionine (SAM) levels in a concentration-dependent manner (IC50 = 20nM), but also selectively inhibits the proliferation of MTAP-deficient HCT116 cells following a 72‑hour treatment [1]. Treatment of AG-270 alone (0.5–4μM, for 48–72 hours) can slightly induce apoptosis of non-small cell lung cancer cells and inhibit their colony formation. AG 270 combined with the methyltransferase like 3 (METTL3) inhibitor STM2457 exhibited a marked synergistic anti tumor effect [4].
In KP4 MTAP-null pancreatic xenografts, oral AG-270 dose-dependently lowered tumor SAM and yielded 67% tumor growth inhibition (TGI) with <5% weight loss, which indicated good tolerability [1].
References:
[1]. Konteatis, Z., et al., Discovery of AG-270, a First-in-Class Oral MAT2A Inhibitor for the Treatment of Tumors with Homozygous MTAP Deletion. Journal of Medicinal Chemistry, 2021. 64(8): p. 4430-4449.
[2]. Hyer, M.L., et al., The MAT2A inhibitor, AG-270, combines with both taxanes and gemcitabine to yield enhanced anti-tumor activity in patient-derived xenograft models. Cancer Research, 2020. 80(16_Supplement): p. 3090-3090.
[3]. Kalev, P., et al., MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage. Cancer Cell, 2021. 39(2): p. 209-224.e11.
[4]. Xuan, Y.F., et al., 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. Biochem Biophys Res Commun, 2024. 716: p. 150011.
AG-270是一种强效、口服活性的甲硫氨酸腺苷转移酶2A（MAT2A）变构抑制剂，其IC50为14nM[1,2]。MAT2A 是一种细胞质酶，已被确定为携带甲硫腺苷磷酸化酶（MTAP）基因缺失的癌症中的合成致死靶点[3]。AG-270 可以诱导合成致死并阻止 MTAP 缺失癌细胞的肿瘤增殖。AG-270 主要应用于肿瘤、免疫系统疾病以及血液和淋巴系统疾病领域。
在HCT116 MTAP缺失细胞中，AG-270处理72小时后可浓度依赖性地降低胞内（S-腺苷蛋氨酸）SAM水平，并选择性抑制MTAP缺失细胞的增殖 [1]。此外，AG-270单药（0.5~4μM）处理48~72小时，可轻度诱导非小细胞肺癌细胞凋亡，并抑制细胞克隆形成。当与甲基转移酶样3（METTL3）抑制剂 STM2457联合使用时，AG-270表现出显著的协同抗肿瘤作用[4]。
在KP4 MTAP缺失胰腺癌异种移植小鼠模型中，AG-270以10 - 200mg/kg的剂量每日一次口服给药，连续给药24-38天。结果显示，AG-270剂量依赖性地降低肿瘤内SAM水平，并使肿瘤生长抑制率达到67%，同时小鼠平均体重下降小于5%，表明耐受性良好[1]。
| Cell experiment [1,2]: | |
Cell lines | HCT-116 and HCT-116 MTAP null cell |
Preparation Method | HCT116 WT and MTAP-/- cells were plated in 96 well tissue culture plates at 20,000 cells per well and allowed to attach overnight at 37°C in 5% CO2. Cells were incubated with AG-270 for 72 hours. After this treatment period, medium was removed and cells were extracted for SAM metabolite measurement by LC-MS/MS. In parallel, both cells were plated at 2,000 cells/well and treated as described above for 96 hours in a cell growth assay. Readout of cell proliferation was obtained by measuring total cellular adenosine triphosphate levels. |
Reaction Conditions | 20, 6.67, 2.22, 0.74, 0.247, 0.082, 0.027, 0.009, 0.003μM; 72 and 96h |
Applications | The SAM levels in HCT116 MTAP-/- cells decreased with increasing concentration after treatment with AG-270 for 72 hours. The growth of MTAP-deficient cells was significantly inhibited (growth percentage dropped from about 100% to about 40%), while WT cells still grew close to 100% at high concentrations after 96 hours of treatment. |
| Animal experiment [1]: | |
Animal models | KP4 MTAP-null xenograft mouse |
Preparation Method | To evaluate the dose-dependent effect of AG-270 in the KP4 xenograft mouse model, KP4 (MTAP‑null human pancreatic cancer cells) were subcutaneously implanted into immunodeficient mice. 60 total animals were randomized into five dose groups (including a control group). AG-270 was administered orally once daily at doses ranging from 10 to 200mg/kg from days 24 to 38. Within 24 hours after the final 200mg/kg dose, tumor samples were collected for pharmacokinetic analysis and SAM level measurement. Tumor volume was monitored regularly to calculate TGI, and body weight was recorded to assess tolerability. |
Dosage form | 10、30、100、200mg/kg; Orally, q.d. for 24-38 days. |
Applications | Treatment with AG-270 resulted in dose-dependent reductions in both tumor SAM levels and tumor growth in KP4 MTAP-null xenografts, with TGI values of 36% at 10mg/kg, 48% at 30mg/kg, 66% at 100mg/kg, and 67% at 200 mg/kg. |
References: | |
| Cas No. | 2201056-66-6 | SDF | |
| 分子式 | C30H27N5O2 | 分子量 | 489.57 |
| 溶解度 | DMSO : 170 mg/mL (347.24 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.0426 mL | 10.213 mL | 20.4261 mL |
| 5 mM | 408.5 μL | 2.0426 mL | 4.0852 mL |
| 10 mM | 204.3 μL | 1.0213 mL | 2.0426 mL |
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