EAI045

Catalog No.S8242 Batch:S824203

Technical Data

Formula	C₁₉H₁₄FN₃O₃S
Molecular Weight	383.40	CAS No.	1942114-09-1
Solubility (25°C)*	In vitro	DMSO	76 mg/mL (198.22 mM)
		Water	Insoluble
		Ethanol	Insoluble
* <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.)

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Biological Activity

Description

EAI045 is an allosteric inhibitor that targets selected drug-resistant EGFR mutants but spares the wild-type receptor.

Targets

EGFR mutants ^[1]

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, EAI045 shows no anti-proliferative effect in the H1975 and H3255 cell lines with concentrations as high as 10μM^[1]. EAI045 inhibits L858R/T790M mutant with an IC50 of 3 nM. However, EAI045 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 EAI045. Since EGFR dimerization is required for kinase enzyme activation, EAI045 may be active against one subunit of an EGFR heterodimer/asymmetric dimer^[2].

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^[1]. When combined with cetuximab that blocks EGFR dimerization, EAI045 markedly reduces tumor growth in a mouse model of L858R/T790M-mutant-driven lung cancer. The mice treated alone with EAI045 do not respond. EAI045 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. EAI045 and cetuximab exhibits mechanistic synergy^[2].

Protocol (from reference)

Cell Assay:^{^[1]}	Cell lines H1975, H3255 and HaCaT cell lines Concentrations Serial dilution (0-100 μM) Incubation Time 3 days Method 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.
Animal Study:^{^[1]}	Animal Models EGFR(TL) (bearing L858R/T790M point mutations) and EGFR(TD) (bearing exon19del/T790M point mutations) mice Dosages 60 mg/kg Administration by oral gavage

Cell Assay:^{^[1]}

Cell lines
H1975, H3255 and HaCaT cell lines
Concentrations
Serial dilution (0-100 μM)
Incubation Time
3 days
Method
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.

Animal Study:^{^[1]}

Animal Models
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

Selleck's 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]	PubMed: 38363422
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]	PubMed: 30396380

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SHIPPING AND STORAGE
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