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| 靶点 |
In terms of potency and selectivity, AZ7550 (compound 28) seems to offer properties that are largely comparable to those of the parent molecule AZD9291. The DM cell line H1975, the AM cell line PC9, and the WT cell line LoVo are all inhibited by AZ7550, with IC50 values of 45, 26, and 786 nM, respectively. The anti-proliferative cell lines H1975 from DM, PC9 from AM, and Calu3 from WT are all inhibited by AZ7550, with GI50 values of 19, 15, and 537 nM, respectively[1].
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| 体外研究 (In Vitro) |
就效力和选择性而言，AZ7550（化合物 28）似乎提供了与母体分子 AZD9291 大致相当的特性。 DM细胞系H1975、AM细胞系PC9和WT细胞系LoVo均被AZ7550抑制，IC50值分别为45、26和786 nM。 DM 的抗增殖细胞系 H1975、AM 的 PC9 和 WT 的 Calu3 均被 AZ7550 抑制，GI50 值分别为 19、15 和 537 nM[1]。
在细胞磷酸化实验中，AZD9291 抑制H1975（DM）细胞中EGFR磷酸化的IC₅₀为15 nM，抑制PC9（AM）细胞中EGFR磷酸化的IC₅₀为17 nM，显示了对突变EGFR的高效力。[1] 在抗增殖实验中，AZD9291 在H1975（DM）细胞中的GI₅₀为24 nM，在PC9（AM）细胞中为23 nM，在Calu3（WT）细胞中为264 nM，证实了对突变驱动细胞的选择性生长抑制。[1] AZD9291 对IGF1R表现出中等活性（IC₅₀ = 2.9 µM），对hERG离子通道亲和力较低（IC₅₀ = 16.2 µM）。[1] 激酶选择性分析（Millipore 270激酶 panel）表明，AZD9291 具有较好的整体选择性，最主要的脱靶活性是针对其他酪氨酸激酶，如IGF1R和INSR。[1] |
| 体内研究 (In Vivo) |
在小鼠异种移植模型中，以10 mg/kg/天的剂量口服给予AZD9291 7天，可在H1975（DM）和PC9（AM）模型中诱导显著的肿瘤消退，同时对A431（WT EGFR）模型影响甚微。[1]
在较低的5 mg/kg/天剂量下给药7天，AZD9291 在H1975和PC9模型中仍显示出优异的疗效。[1] 在携带H1975或PC9异种移植瘤的小鼠中，单次口服AZD9291（10 mg/kg）可导致肿瘤中EGFR磷酸化（p-EGFR）的深度且持续抑制，时间长达24小时。[1] 在大鼠毒理学研究中，单次200 mg/kg口服剂量的AZD9291 未引起血糖或胰岛素水平的显著变化，这与其它引起高血糖和高胰岛素血症的候选化合物形成对比。[1] |
| 细胞实验 |
细胞磷酸化实验： 用化合物处理细胞（如H1975、PC9、Calu3）2小时。孵育后，裂解细胞，并使用ELISA试剂盒测量EGFR磷酸化水平。生成剂量反应曲线以计算抑制磷酸化的IC₅₀值。[1]
抗增殖实验： 接种细胞并使其贴壁。加入化合物的系列稀释液，孵育指定时间（通常为数天）。使用合适的终点检测法（如ATP含量）测量细胞活力或生长抑制情况。根据剂量反应曲线计算导致50%生长抑制的浓度（GI₅₀）。[1] |
| 动物实验 |
Mouse Xenograft Efficacy Studies: Immune-compromised mice were inoculated subcutaneously with human tumor cell lines (H1975, PC9, or A431). Once tumors reached a predetermined volume, mice were randomized into treatment groups. AZD9291 was administered orally once daily (q.d.) as a suspension in 0.5% hydroxypropyl methylcellulose (HPMC) / 0.1% Tween in deionized water. Tumor volumes were measured regularly, and percent tumor growth inhibition (%TGI) or regression was calculated compared to the vehicle control group. [1]
Mouse Pharmacodynamic (PD) Studies: Mice bearing established H1975 or PC9 xenografts received a single oral dose of AZD9291 (e.g., 10 mg/kg) formulated as above. Groups of mice were euthanized at various time points post-dose (e.g., 1, 6, 16, 24, 30 hours). Tumors were excised, homogenized, and analyzed for levels of phosphorylated EGFR (p-EGFR) and total EGFR, typically using ELISA, to determine the percentage inhibition of p-EGFR. [1] Rat Toxicology Study: Rats received a single oral dose of AZD9291 (200 mg/kg) as a suspension in 0.5% HPMC/0.1% Tween. Blood samples were collected over a 24-hour period for measurement of glucose and insulin levels to assess effects on the glucose/insulin axis. [1] Guinea Pig Cardiovascular Safety Study: Compounds were assessed in an in vivo guinea pig model to evaluate effects on hemodynamic, ECG, and contractility parameters, including QT interval prolongation. [1] |
| 药代性质 (ADME/PK) |
In rats, AZD9291 had a low to moderate intravenous clearance (CL) of 45 mL/min/kg and low oral bioavailability (F) of 16% at a 5 mg/kg dose. [1]
In mice, following a 10 mg/kg oral dose, AZD9291 achieved an AUC of 1.4 µM·h and a Cmax of 0.38 µM. [1] AZD9291 exhibited low plasma protein binding in various species: rat (16% free), human (2.9% free), and mouse (7.5% free). [1] The major circulating metabolites of AZD9291 in vivo were identified as the desmethyl metabolite (27, formed by loss of the indole N-methyl group) and a side-chain dealkylation product (28). In mice dosed with AZD9291, metabolite 27 was present at lower concentrations than the parent but had higher cellular potency and lower protein binding, contributing to overall efficacy. [1] In vitro intrinsic clearance in rat and human hepatocytes was relatively low (rat: 27 µL/min/10⁶ cells; human: <3 µL/min/10⁶ cells). [1] |
| 毒性/毒理 (Toxicokinetics/TK) |
In a rat toxicology study, a single 200 mg/kg oral dose of AZD9291 did not cause significant hyperglycemia or hyperinsulinemia, unlike comparator compounds. This was attributed to its weaker inhibition of IGF1R and INSR (INSR IC₅₀ = 0.912 µM). [1]
In a guinea pig cardiovascular safety model, AZD9291 did not show pronounced QT prolongation at free Cmax concentrations, consistent with its lower hERG channel affinity (IC₅₀ = 16.2 µM) compared to other candidates. [1] The formation of the active metabolite 27, which has a narrower wild-type EGFR selectivity margin, was identified as a potential risk factor for wild-type EGFR-driven toxicity (e.g., rash, diarrhea). However, early clinical data indicated manageable tolerability. [1] |
| 参考文献 | |
| 其他信息 |
AZD9291 is a third-generation EGFR TKI designed to overcome T790M-mediated resistance in non-small cell lung cancer (NSCLC) while minimizing wild-type EGFR-related toxicities. [1]
It functions as an irreversible inhibitor by covalently binding to the cysteine-797 residue in the EGFR kinase domain. [1] AZD9291 mesylate salt was selected for clinical development over the free base due to manufacturing and physical form considerations. The mesylate salt showed comparable pharmacokinetics to the free base. [1] Based on preclinical efficacy and safety profiles, AZD9291 was selected as a clinical candidate. The first-in-human dose was set at 20 mg orally once daily. [1] Preliminary clinical data from a phase I trial (AURA) in patients with EGFRm+ advanced NSCLC who had progressed on prior EGFR TKIs showed encouraging tumor responses (e.g., ~40-60% tumor shrinkage) and a manageable safety profile with no severe rash events and only low-grade diarrhea reported. [1] |
| 分子式 |
C28H35N7O5S
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|---|---|
| 分子量 |
581.686404466629
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| 精确质量 |
773.218
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| CAS号 |
2319837-99-3
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| 相关CAS号 |
AZ7550;1421373-99-0;AZ7550 hydrochloride;2309762-40-9
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| PubChem CID |
134611624
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| 外观&性状 |
Light yellow to yellow solid powder
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| tPSA |
285
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| 氢键供体(HBD)数目 |
6
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| 氢键受体(HBA)数目 |
16
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| 可旋转键数目(RBC) |
10
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| 重原子数目 |
51
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| 分子复杂度/Complexity |
817
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| 定义原子立体中心数目 |
0
|
| SMILES |
S(O)(=O)(=O)C.CN1C2=CC=CC=C2C(C2C=CN=C(NC3C=C(NC(=O)C=C)C(N(C)CCNC)=CC=3OC)N=2)=C1
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| InChi Key |
AZRGPJKRGFXCLD-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H31N7O2.3CH4O3S/c1-6-26(35)30-21-15-22(25(36-5)16-24(21)33(3)14-13-28-2)32-27-29-12-11-20(31-27)19-17-34(4)23-10-8-7-9-18(19)23;3*1-5(2,3)4/h6-12,15-17,28H,1,13-14H2,2-5H3,(H,30,35)(H,29,31,32);3*1H3,(H,2,3,4)
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| 化学名 |
methanesulfonic acid;N-[4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]-2-[methyl-[2-(methylamino)ethyl]amino]phenyl]prop-2-enamide
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| 别名 |
AZ7550 Mesylate; AZ 7550; AZ-7550
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| 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 注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。 |
| 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 : ~25 mg/mL (~32.30 mM)
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|---|---|
| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.5 mg/mL (3.23 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 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；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: ≥ 2.5 mg/mL (3.23 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 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，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 | 1.7191 mL | 8.5956 mL | 17.1913 mL | |
| 5 mM | 0.3438 mL | 1.7191 mL | 3.4383 mL | |
| 10 mM | 0.1719 mL | 0.8596 mL | 1.7191 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) 。
AZD9291 binding mode and structure.Cancer Discov.2014 Sep;4(9):1046-61. |
Effect of AZD9291 on EGFR phosphorylationin vitro.Cancer Discov.2014 Sep;4(9):1046-61. |
In vivoanti-tumor efficacy of AZD9291 in subcutaneous xenograft models of EGFR-TKI sensitising and T790M resistant lung cancer.Cancer Discov.2014 Sep;4(9):1046-61. |
AZD9291 induces significant and sustained tumor regression in transgenic models of EGFR-TKI sensitising (C/L858R) and T790M resistant (C/L+T) lung cancer.Cancer Discov.2014 Sep;4(9):1046-61. |
AZD9291 inhibits EGFR phosphorylation and downstream signallng in murine models of EGFR T790M resistant lung cancer.Cancer Discov.2014 Sep;4(9):1046-61. |
Proof of concept clinical studies validating AZD9291 as a mutant-selective EGFR kinase T790M inhibitor.Cancer Discov.2014 Sep;4(9):1046-61. |
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