In Vivo (Add solvents to the product individually and in order.)
Homogeneous suspension
CMC-NA
≥5mg/ml
Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. * Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)
Preparing Stock Solutions
Biological Activity
Description
EAI045 is an allosteric inhibitor that targets selected drug-resistant EGFR mutants but spares the wild-type receptor.
Targets
EGFR mutants
In vitro
EAI045 potently inhibits EGFR Y1173 phosphorylation in H1975 cells (half maximal effective concentration (EC50)=2nM), but not in HaCaT cells, a keratinocyte cell line with wild-type EGFR. Despite potent inhibition of mutant EGFR, this compound shows no anti-proliferative effect in the H1975 and H3255 cell lines with concentrations as high as 10μM. It inhibits L858R/T790M mutant with an IC50 of 3 nM. However, this compound is not able to completely abolish EGFR autophosphorylation in H1975 NSCLC cell line harboring the L858R/T790M mutant. Dimerization-defective/independent mutants are markedly more sensitive to it. Since EGFR dimerization is required for kinase enzyme activation, this chemical may be active against one subunit of an EGFR heterodimer/asymmetric dimer.
In Vivo
Mouse pharmacokinetic studies with EAI045 reveals a maximal plasma concentration of 0.57μM, a half-life of 2.15 h, and oral bioavailability of 26% after dosing at 20mg/kg. When combined with cetuximab that blocks EGFR dimerization, this compound markedly reduces tumor growth in a mouse model of L858R/T790M-mutant-driven lung cancer. The mice treated alone with this chemical do not respond. It in combination with cetuximab also induces marked tumor shrinkage in the mouse model carrying L858R/T790M/C797S, a mutant known to be resistant to all third-generation EGFR TKIs. This compound and cetuximab exhibits mechanistic synergy.
H1975, H3255 and HaCaT cell lines are plated in solid white 384-well plates at 500 cells per well in 10% FBS RPMI penicillin/streptomycin media. Using a Pin Tool, 50 nl of serial diluted compounds are transferred to the cells. After 3 days, cell viability is measured.
EGFR(TL) (bearing L858R/T790M point mutations) and EGFR(TD) (bearing exon19del/T790M point mutations) mice
Dosages
60 mg/kg
Administration
by oral gavage
References
https://pubmed.ncbi.nlm.nih.gov/27251290/
https://pubmed.ncbi.nlm.nih.gov/27448564/
Sellecks EAI045 Has Been Cited by 2 Publications
Synthesis and preclinical evaluation of [11C]EAI045 as a PET tracer for imaging tumors expressing mutated epidermal growth factor receptor
[ EJNMMI Res, 2024, 14(1):19]
An UPLC-MS/MS method for the determination of EAI045 in plasma and tissues and its application to pharmacokinetic and distribution studies in rats.
[ Pharmazie, 2018, 73(11):630-634]
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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.
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