EAI045
目录号 : GC12281
A potent inhibitor of mutant EGFRs
Cas No.:1942114-09-1
Sample solution is provided at 25 µL, 10mM.
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EAI045 is an allosteric inhibitor that targets selected drug-resistant EGFR mutants but spares the wild-type receptor.
EGFR (epidermal growth factor receptor) is a cell-surface receptor tyrosine kinase. The receptor activation leads to dimerization and tyrosine autophosphorylation. It induces a cascade of downstream cellular responses such as modification in gene expression, cell proliferation and cytoskeletal rearrangement etc.
EAI1045 has an IC50 of 3 nM against the L858R/T790M mutant with a 1000-fold selectivity over wild-type EGFR at 1 mM ATP. In combination with 10 μg/ml cetuximab, EAI045 inhibited proliferation of EGFR (L858R/T790M) Ba/F3 cells with an IC50 of approximately 10nM.
In mice treated with EAI045 at 60 mg kg−1 by oral gavage once daily, combined treatment with cetuximab (1 mg intraperitoneally every other day) showed prominent tumour regressions, but these treated with EAI045 alone did not respond to the treatment.
Pharmacodynamic studies in exon19del/T790M and L858R/T790M/C797S mice indicated combined treatment of EAI045 with cetuximab effectively inhibited phosphorylation of EGFR and downstream signalling proteins in those mice, but not in mice with insensitive exon19del/T790M mutation.
Reference:
1. Jia Y, Yun CH, Park E et al.Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature. 2016 May 25;534(7605):129-32.
| Cell experiment [1]: | |
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Cell lines |
EGFR mutant cell lines (H1975 and H3255); HaCaT cells |
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Preparation method |
This compound is soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
0-100 μM; 3 days |
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Applications |
In H1975 cells, EAI045 potently decreased, but did not completely eliminate EGFR autophosphorylation and potently inhibited EGFR Y1173 phosphorylation with EC50 value of 2 nM. In the H1975 and H3255 cell lines, EAI045 (10 μM) showed no anti-proliferative effect. EAI045 inhibited proliferation of L858R/T790M and L858R mutant cells, but not the exon19del/T790M or parental Ba/F3 cells, suggesting the on-target, mutant selective activity. |
| Animal experiment [1]: | |
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Animal models |
EGFR-TL (L858R/T790M) and EGFR-TD (exon19del/T790M) mice |
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Dosage form |
60 mg/kg daily by oral gavage; dissolved in 10% NMP (10% 1-methyl-2-pyrrolidinone: 90% PEG-300); 4-weeks |
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Application |
In EGFR L858R/T790M-mutant lung cancer mouse model, EAI045 revealed a maximal plasma concentration of 0.57 μM, a half-life of 2.15 h, and oral bioavailability of 26% after dosing at 20 mg/kg. The combination of EAI045 (60 mg/kg) and cetuximab exhibited striking tumor regressions. EAI045 in combination with cetuximab effectively inhibited phosphorylation of EGFR and downstream signaling proteins. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. Jia Y, Yun CH, Park E et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature. 2016 May 25;534(7605):129-32. | |
| Cas No. | 1942114-09-1 | SDF | |
| 化学名 | (Z)-2-(5-fluoro-2-hydroxyphenyl)-2-(1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetimidic acid | ||
| Canonical SMILES | FC1=CC(C(N2CC3=CC=CC=C3C2=O)/C(O)=N/C4=NC=CS4)=C(O)C=C1 | ||
| 分子式 | C19H14FN3O3S | 分子量 | 383.40 |
| 溶解度 | ≥ 38.3mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 2.6082 mL | 13.0412 mL | 26.0824 mL |
| 5 mM | 0.5216 mL | 2.6082 mL | 5.2165 mL |
| 10 mM | 0.2608 mL | 1.3041 mL | 2.6082 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
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，
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 saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet