Home Protein Tyrosine Kinase EGFR inhibitor Zorifertinib (AZD3759)

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Zorifertinib (AZD3759) EGFR inhibitor

Cat.No.S7971

Zorifertinib (AZD3759) is a potent, oral active, CNS-penetrant EGFR inhibitor with IC50 values of 0.3 nM, 0.2 nM, and 0.2 nM for EGFR (WT), EGFR (L858R), and EGFR (exon 19Del), respectively. This compound is in Phase 1.
Zorifertinib (AZD3759) EGFR inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 459.90

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Quality Control

Cell Culture, Treatment & Working Concentration

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
H3255 cells Proliferation assay 72 h Antiproliferative against human H3255 cells expressing EGFR L858R mutant after 72 hrs by MTS assay, IC50=0.007 μM
PC9 cells Function assay Inhibition of EGFR exon19 deletion mutant phosphorylation in human PC9 cells, IC50=0.0074 μM
H838 cells Function assay Inhibition of EGFR phosphorylation in human H838 cells, IC50=0.0645 μM
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Chemical Information, Storage & Stability

Molecular Weight 459.90 Formula

C22H23ClFN5O3

 Storage (From the date of receipt)
CAS No. 1626387-80-1 Download SDF Storage of Stock Solutions

Synonyms N/A Smiles CC1CN(CCN1C(=O)OC2=C(C=C3C(=C2)C(=NC=N3)NC4=C(C(=CC=C4)Cl)F)OC)C

Solubility

In vitro
Batch:

DMSO : 91 mg/mL (197.86 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Ethanol : 20 mg/mL

Water : Insoluble

Molarity Calculator

Mass Concentration Volume Molecular Weight

In vivo
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Working concentration: mg/ml;

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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.

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Mechanism of Action

Targets/IC50/Ki
EGFR (L858R) [1]
(Cell-free assay)
0.2 nM
EGFR (exon 19Del) [1]
(Cell-free assay)
0.2 nM
EGFR (WT) [1]
(Cell-free assay)
0.3 nM
In vitro
在H3255 (L858R)细胞中，Zorifertinib (AZD3759)抑制EGFR磷酸化的IC50为7.2 nM。该化合物对pEGFR通路和EGFR突变衍生细胞PC-9及H3255的增殖均表现出抑制作用，IC50分别为7.7 nM和7 nM，但对H838细胞的增殖无显著活性。[1]
Kinase Assay
IC50 determination of compounds against EGFR enzymes
The inhibition potency of Zorifertinib (AZD3759) against EGFR WT and mutant enzymes is assessed using CisBio homogenous time resolved fluorescence approach (HTRF, Cat No. 62TK0PEJ) according to manufacturer’s instruction. The final enzyme concentrations used in this assay are 0.1 nM, 0.03 nM, and 0.026 nM for EGFR wild type, L858R and Exon19Del, respectively, and 0.8 μM, 4 μM and 25 μM ATP, corresponding to the Km values of EGFR enzymes, are applied accordingly. In brief, 3 μL of ATP and 2 μM TK biotin-peptide substrate are incubated in the presence or absence of serially diluted compound at room temperature in 384-well Greiner white polystyrene assay plates. The reaction is initiated by addition of 3 μL kinase which could phosphorylate the substrate peptide, and the assay buffer contains 1 mM DTT, 5 mM MgCl2, 1 mM MnCl2, and 0.01% CHAPS. After 30 minutes incubation, the reaction is stopped by the addition of 6 μl detection reagent mix containing 250 nM Strep-XL665 and TK Ab Europium Cryptate diluted in detection buffer. The plates are incubated for 1 h before the fluorescence is then measured at 615 nm and 665 nm, respectively with excitation wavelength at 320 nm by EnVision Multilabel Reader from Perkin Elmer using standard HTRF settings. The calculated signal ratio of 665 nm/615 nm is proportional to the kinase activity. The concentration of this compound producing 50% inhibition of the respective kinase (IC50) is calculated using four-parameter logistic fit.
In vivo
Zorifertinib (AZD3759) shows good oral bioavailability in dogs and penetrates extensively into monkey brain. In a brain metastasis PC-9 (Exon19Del) model, this compound (15 mg/kg) causes significant dose-dependent antitumor efficacy. [1]
References

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02228369 Completed
EGFR Mutation Positive Advanced Non Small Cell Lung Cancer
AstraZeneca
 November 5 2014 Phase 1

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