Home Protein Tyrosine Kinase EGFR inhibitor Zorifertinib (AZD3759) For research use only.

Zorifertinib (AZD3759)

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

Zorifertinib (AZD3759) Chemical Structure

Zorifertinib (AZD3759) Chemical Structure

CAS No. 1626387-80-1

Purity & Quality Control

Zorifertinib (AZD3759) Related Products

Signaling Pathway

EGFR Signaling Pathways

EGFR Signaling Pathway

Cell Data

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 26313252
PC9 cells Function assay Inhibition of EGFR exon19 deletion mutant phosphorylation in human PC9 cells, IC50=0.0074 μM 26313252
H838 cells Function assay Inhibition of EGFR phosphorylation in human H838 cells, IC50=0.0645 μM 26313252
Click to View More Cell Line Experimental Data

Biological Activity

Description Zorifertinib (AZD3759) is a potent, oral active, CNS-penetrant EGFR inhibitor with IC50 of 0.3 nM, 0.2 nM, and 0.2 nM for EGFR (WT), EGFR (L858R), and EGFR (exon 19Del), respectively. Phase 1.
Targets
EGFR (L858R) [1]
(Cell-free assay)		 EGFR (exon 19Del) [1]
(Cell-free assay)		 EGFR (WT) [1]
(Cell-free assay)
0.2 nM 0.2 nM 0.3 nM
In vitro
In vitro In H3255 (L858R) cells, AZD3759 inhibits EGFR phosphorylation with IC50 of 7.2 nM. AZD3759 demonstrates inhibitory effects on both the pEGFR pathway and cell proliferation of EGFR mutation-derived cells PC-9 and H3255 with IC50 of 7.7 nM and 7 nM, respectively, showing mo activity on cell proliferation of H838 cells. [1]
Kinase Assay IC50 determination of compounds against EGFR enzymes
The inhibition potency of compounds 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 compound producing 50% inhibition of the respective kinase (IC50) is calculated using four-parameter logistic fit.
Cell Research Cell lines PC-9 (exon 19Del), H3255 (L858R) and H838 (wt) cells
Concentrations ~30 mM
Incubation Time 72 h
Method Cell proliferation assay is determined by MTS methods. Briefly, cells are seeded in 96-well plates (at a density to allow for logarithmic growth during the 72-hour assay) and incubated overnight at 37 °C and 5% CO2. Cells are then exposed to concentrations of compounds ranging from 30 to 0.0003 mM for 72 hours. For the MTS endpoint, cell proliferation is measured by the CellTiter AQueous Non-Radioactive Cell Proliferation Assay reagent in accordance with the manufacturer’s protocol. Absorbance is measured with a Tecan Ultra instrument. Predose measurements are made, and concentration needed to reduce the growth of treated cells to half that of untreated cells (GI50) values are determined using absorbance readings.
In Vivo
In vivo AZD3759 shows good oral bioavailability in dogs, and penetrates extensively into monkey brain. In a brain metastasis PC-9 (Exon19Del) model, AZD3759 (15 mg/kg) causes significant dose-dependent antitumor efficacy. [1]
Animal Research Animal Models Mice bearing PC-9 (Exon19Del) tumors
Dosages ~15 mg/kg
Administration p.o.
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

Chemical Information & Solubility

Molecular Weight 459.90 Formula

C22H23ClFN5O3
CAS No. 1626387-80-1 SDF Download Zorifertinib (AZD3759) SDF
Smiles CC1CN(CCN1C(=O)OC2=C(C=C3C(=C2)C(=NC=N3)NC4=C(C(=CC=C4)Cl)F)OC)C
Storage (From the date of receipt)

In vitro
Batch:

DMSO : 91 mg/mL ( (197.86 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 20 mg/mL

Water : Insoluble


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In vivo
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Tech Support

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