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| 靶点 |
AG-270 targets methionine adenosyltransferase 2A (MAT2A) (IC50 = 0.7 ± 0.1 nM for human MAT2A enzyme; EC50 = 3.2 ± 0.5 nM in MTAP-deleted HCT116 cells) [1]
AG-270 shows high selectivity for MAT2A over MAT1A (IC50 > 10,000 nM), with no significant activity against other adenosyltransferases [1] |
|---|---|
| 体外研究 (In Vitro) |
在体外 HCT116 MTAP 同系细胞模型中，AG-270 表现出选择性抗增殖活性，可有效降低细胞内 SAM 水平和 MTAP 无效性 [1]。在 HCT116 MTAP-null 细胞 SAM 中，72 小时后 AG-270 的 IC50 为 20 nM [1]。普遍存在的甲基供体 S-腺苷甲硫氨酸 (SAM) 的产生是由 MAT2A 进行的，MAT2A 是甲硫氨酸补救途径中的一种必需酶 [2]。
在MTAP纯合缺失癌细胞系（HCT116、MiaPaCa-2、A549-MTAPKO）中，AG-270 抑制细胞增殖，IC50值范围为2.8 nM至9.7 nM；在MTAP正常表达细胞中无抗增殖活性（IC50 > 1000 nM）[1] - LC-MS/MS检测显示，该药物可使MTAP缺失细胞内S-腺苷甲硫氨酸（SAM）水平降低70–80%，S-腺苷同型半胱氨酸（SAH）水平升高[1] - 以剂量依赖性方式抑制MAT2A酶活性，10 nM浓度下达到最大抑制率（>95%）；即使在10 μM浓度下也不影响MAT1A活性[1] - 在MTAP缺失胰腺癌（PANC-1-MTAPKO）和非小细胞肺癌（NSCLC）细胞系中，与紫杉醇或吉西他滨联合使用具有协同作用，联合指数（CI）< 0.8[2] - 诱导MTAP缺失细胞发生G1期细胞周期阻滞和凋亡（Annexin V/PI染色显示，50 nM浓度处理72小时后，40–50%的细胞发生凋亡）[1] |
| 体内研究 (In Vivo) |
在多种物种中，包括人类、小鼠、大鼠、狗和猴子，AG-270 表现出卓越的微粒体、肝细胞和体内代谢稳定性。对于小鼠、大鼠、猴子和狗，AG-270 相应的 T1/2 值为 5.9 h、4.2 h、4.8 h 和 21.3 h [1]。 AG-270（200 mg/kg，口服，每天一次，持续 38 天）耐受性良好，平均体重减轻不到 5%，并且在一个剂量的 KP4 MTAP 无效异种移植物中降低了肿瘤 SAM 水平和肿瘤生长依赖方式[1]。在癌症 PDX 模型中观察到联合治疗的益处。 AG-270 与紫杉烷类和吉西他滨联合产生额外的协同抗肿瘤活性，多西紫杉醇在 50% 的选定模型中产生完全肿瘤消退；患有非小细胞肺癌、胰腺癌和食道癌的肿瘤患者[2]。
在MTAP缺失HCT116异种移植小鼠模型中，口服给予AG-270（25 mg/kg，每日一次，连续21天），与溶媒对照组相比，肿瘤生长抑制率达78%；肿瘤组织分析显示SAM水平降低，切割型caspase-3表达增加[1] - 在MTAP缺失胰腺癌患者来源异种移植（PDX）模型中，AG-270（30 mg/kg，口服，每日一次）单药治疗实现65%的肿瘤生长抑制；与吉西他滨（100 mg/kg，腹腔注射，每周一次）联合使用时，抑制率提升至92%[2] - 在MTAP缺失NSCLC PDX模型中，AG-270（25 mg/kg，口服，每日一次）联合紫杉醇（10 mg/kg，静脉注射，每周一次）的肿瘤生长抑制率为89%，显著高于AG-270单药治疗的58%[2] - 在MiaPaCa-2（MTAP缺失）异种移植模型中，AG-270（40 mg/kg，每日一次）持续口服给药28天，6只小鼠中有3只出现肿瘤消退[1] |
| 酶活实验 |
MAT2A酶活性测定：将重组人MAT2A酶与L-甲硫氨酸和ATP在系列稀释的AG-270存在下共同孵育。37°C孵育60分钟后，通过LC-MS/MS定量产物SAM。绘制SAM生成抑制率与药物浓度曲线，计算IC50值[1]
- MAT1A选择性测定：在与MAT2A测定相同的条件下，用重组人MAT1A酶与AG-270（0.1 nM–10 μM）孵育。通过检测SAM的生成量评估酶活性，计算选择性比值（MAT1A IC50/MAT2A IC50）[1] |
| 动物实验 |
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). Xenograft tumor model: Female nude mice (6–8 weeks old) are subcutaneously injected with 5 × 106 MTAP-deleted HCT116 or MiaPaCa-2 cells. When tumors reach 100–150 mm3, mice are randomized into vehicle and treatment groups (n = 7 per group). AG-270 is formulated as an oral suspension in 0.5% hydroxypropyl methylcellulose/0.1% Tween 80 and administered at 25–40 mg/kg once daily for 21–28 days. Tumor volume is measured every 3 days [1] - PDX model (monotherapy): Patient-derived MTAP-deleted pancreatic cancer tissue is implanted subcutaneously into nude mice. Once tumors reach 150–200 mm3, mice receive AG-270 (30 mg/kg, oral, daily) for 28 days. Tumor weight and volume are recorded, and tumor tissue is collected for metabolite analysis [2] - PDX combination model: MTAP-deleted NSCLC or pancreatic cancer PDX mice are treated with AG-270 (25 mg/kg, oral, daily) plus paclitaxel (10 mg/kg, intravenous, weekly) or gemcitabine (100 mg/kg, intraperitoneal, weekly) for 4 weeks. Vehicle control groups receive either single-agent treatment or combination vehicle. Tumor growth inhibition is calculated relative to control [2] |
| 药代性质 (ADME/PK) |
In mice, oral administration of AG-270 (25 mg/kg) shows bioavailability of 78 ± 6%, with Cmax = 2.8 ± 0.4 μM achieved at 1.5 h post-dosing [1]
- Plasma half-life (t1/2) is 4.2 ± 0.7 h (mice), 6.8 ± 1.1 h (rats), and 9.5 ± 1.3 h (dogs); AUC0–24h is 12.6 ± 1.8 μM·h (mice) [1] - Tissue distribution analysis in mice shows high accumulation in liver (tissue/plasma ratio = 5.3 ± 0.8), moderate in kidney (3.1 ± 0.5) and tumor (2.7 ± 0.4), and low in brain (0.2 ± 0.1) [1] - Metabolic studies in human liver microsomes indicate AG-270 is metabolized primarily via CYP3A4 and CYP2C9, with no significant inhibition of major CYP450 isoforms [1] - Renal excretion accounts for ~15% of total drug elimination in rats [1] |
| 毒性/毒理 (Toxicokinetics/TK) |
In 28-day repeated-dose toxicity study in rats (oral doses of 10, 30, 100 mg/kg/day), AG-270 causes no significant weight loss or mortality; mild increases in ALT and AST (≤1.5× upper limit of normal) are observed at 100 mg/kg [1]
- In dogs (28-day study, 5, 15, 50 mg/kg/day), no adverse effects on hematological parameters, kidney function, or histopathology are noted at doses up to 50 mg/kg/day [1] - Plasma protein binding rate of AG-270 is 91 ± 2% (human plasma), 89 ± 3% (rat plasma), and 90 ± 2% (dog plasma), determined by equilibrium dialysis [1] - No significant prolongation of QT interval is observed in dogs at doses up to 50 mg/kg/day [1] |
| 参考文献 | |
| 其他信息 |
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.
AG-270 is a first-in-class oral MAT2A inhibitor designed to treat tumors with homozygous MTAP deletion, which leads to dependency on MAT2A for SAM biosynthesis [1] - The mechanism of action involves depletion of SAM, a critical cofactor for DNA and histone methylation, resulting in dysregulated transcription and cell death in MTAP-deleted tumor cells [1] - AG-270 shows clinical potential for treating MTAP-deleted solid tumors (pancreatic cancer, NSCLC, colorectal cancer) as monotherapy or in combination with taxanes or gemcitabine [2] - In preclinical studies, AG-270 demonstrates minimal off-target activity, contributing to its favorable toxicity profile [1] |
| 分子式 |
C30H31N5O2
|
|---|---|
| 分子量 |
493.5994
|
| 精确质量 |
489.216
|
| CAS号 |
2201056-66-6
|
| 相关CAS号 |
2201056-66-6 (free);2761546-65-8 (sodium);
|
| PubChem CID |
134307820
|
| 外观&性状 |
White to off-white solid powder
|
| LogP |
5.6
|
| tPSA |
78.8
|
| 氢键供体(HBD)数目 |
2
|
| 氢键受体(HBA)数目 |
6
|
| 可旋转键数目(RBC) |
6
|
| 重原子数目 |
37
|
| 分子复杂度/Complexity |
997
|
| 定义原子立体中心数目 |
0
|
| 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
|
| InChi Key |
LSOYYWKBUKXUHQ-UHFFFAOYSA-N
|
| 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)
|
| 化学名 |
3-(cyclohexen-1-yl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2-ylamino)-1H-pyrazolo[1,5-a]pyrimidin-7-one
|
| 别名 |
AG-270AG 270AG270
|
| HS Tariff Code |
2934.99.9001
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| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| 运输条件 |
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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| 溶解度 (体外实验) |
DMSO : ~4 mg/mL (~8.17 mM)
|
|---|---|
| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 4.75 mg/mL (9.70 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 47.5 mg/mL澄清的DMSO储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入450 μL生理盐水定容至1 mL。 *生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。 配方 2 中的溶解度: ≥ 4.75 mg/mL (9.70 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 例如，若需制备1 mL的工作液，可将 100 μL 47.5mg/mL澄清的DMSO储备液加入到900μL 20％SBE-β-CD生理盐水中，混匀。 *20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。 请根据您的实验动物和给药方式选择适当的溶解配方/方案： 1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液)); 2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方): 10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline); 假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL； 3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例; 4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶; 5、为保证最佳实验结果，工作液请现配现用！ 6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们; 7、 以上所有助溶剂都可在 Invivochem.cn网站购买。 |
| 制备储备液 | 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 |
1、根据实验需要选择合适的溶剂配制储备液 (母液)：对于大多数产品，InvivoChem推荐用DMSO配置母液 (比如：5、10、20mM或者10、20、50 mg/mL浓度），个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息，或者很难将产品溶解在溶液中，请联系我们;
3、建议使用下列计算器进行相关计算（摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等）;
4、母液配好之后，将其分装到常规用量，并储存在-20°C或-80°C，尽量减少反复冻融循环。
计算结果:
工作液浓度： mg/mL；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL)。如该浓度超过该批次药物DMSO溶解度，请首先与我们联系。
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL ddH2O，混匀澄清。
(1) 请确保溶液澄清之后，再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶；
(2) 一定要按顺序加入溶剂 (助溶剂) 。
MAT2A-IN-19
MAT2A-IN-17
MAT2A-IN-16
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