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EAI045

Catalog No.GC12281

Inhibitor of L858R/T790M EGFR mutants

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EAI045 Chemical Structure

Cas No.: 1942114-09-1

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10mg
$39.00
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25mg Please Inquire Please Inquire
100mg
$225.00
In stock

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Sample solution is provided at 25 µL, 10mM.

Product Documents

Quality Control & SDS

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Protocol

Cell experiment [1]:

Cell lines

EGFR mutant cell lines (H1975 and H3255); HaCaT cells

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.

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.

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.

Background

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.

Chemical Properties

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.
Shipping Condition Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.

Complete Stock Solution Preparation Table

Prepare stock solution
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
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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.

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Average Rating: 5 ★★★★★ (Based on Reviews and 30 reference(s) in Google Scholar.)

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