AG-270

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. AG270 combined with the methyltransferase like 3 (METTL3) inhibitor STM2457 exhibited a marked synergistic antitumor 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]。