EAI045 |
| Catalog No.GC12281 |
EAI045는 10μM ATP에서 EGFR, EGFRL858R, EGFRT790M 및 EGFRL858R/T790M에 대해 IC50이 각각 1.9, 0.019, 0.19 및 0.002μM인 돌연변이 EGFR의 알로스테릭 및 4세대 억제제입니다.
Products are for research use only. Not for human use. We do not sell to patients.
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. |
|
Reacting condition |
0-100 μM; 3 days |
|
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]: | |
|
Animal models |
EGFR-TL (L858R/T790M) and EGFR-TD (exon19del/T790M) mice |
|
Dosage form |
60 mg/kg daily by oral gavage; dissolved in 10% NMP (10% 1-methyl-2-pyrrolidinone: 90% PEG-300); 4-weeks |
|
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 | |
| Chemical Name | (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 | ||
| Formula | C19H14FN3O3S | M.Wt | 383.4 |
| Solubility | ≥ 38.3mg/mL in DMSO | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
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| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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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 |
Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)
g
μL
Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)
Calculation results:
Working concentration: mg/ml;
Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )
Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
3. All of the above co-solvents are available for purchase on the GlpBio website.
Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 30 reference(s) in Google Scholar.)
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