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    Zorifertinib (AZD3759; AZD-3759; zorifertinibum)
    Zorifertinib (AZD3759; AZD-3759; zorifertinibum)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0538
    CAS #: 1626387-80-1Purity ≥98%

    Description: Zorifertinib (formerly AZD3759; AZD-3759; zorifertinibum) is a novel, potent, orally bioavailable, CNS (central nervous system)-penetrant EGFR (epidermal growth factor receptor) inhibitor with potential antitumor activity. It inhibits EGFR (WT), EGFR (L858R), and EGFR (exon 19Del) with IC50s of 0.3 nM, 0.2 nM, and 0.2 nM, respectively. AZD3759 binds to and inhibits the activity of EGFR as well as certain mutant forms of EGFR. This prevents EGFR-mediated signaling, and may lead to both induction of cell death and inhibition of tumor growth in EGFR-overexpressing cells. In summary, AZD3759 is an investigational anticaner drug that is currently in Phase 1 clinical trial, and has excellent central nervous system penetration and which induces profound regression of brain metastases in a mouse model.

    References: J Med Chem. 2015 Oct 22;58(20):8200-15

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    Molecular Weight (MW)459.90
    FormulaC22H23ClFN5O3
    CAS No.1626387-80-1
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 92 mg/mL (200.0 mM)
    Water: <1 mg/mL
    Ethanol: 44 mg/mL (95.7 mM)
    SMILESO=C(N1[[email protected]](C)CN(C)CC1)OC2=CC3=C(NC4=CC=CC(Cl)=C4F)N=CN=C3C=C2OC
    Synonymszorifertinibum; zorifertinib; AZD3759; AZD-3759; AZD 3759 

    Chemical Name: (R)-4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl 2,4-dimethylpiperazine-1-carboxylate

    InChi Key: MXDSJQHFFDGFDK-CYBMUJFWSA-N

    InChi Code: InChI=1S/C22H23ClFN5O3/c1-13-11-28(2)7-8-29(13)22(30)32-19-9-14-17(10-18(19)31-3)25-12-26-21(14)27-16-6-4-5-15(23)20(16)24/h4-6,9-10,12-13H,7-8,11H2,1-3H3,(H,25,26,27)/t13-/m1/s1

    SMILES Code: O=C(N1[[email protected]](C)CN(C)CC1)OC2=CC3=C(NC4=CC=CC(Cl)=C4F)N=CN=C3C=C2OC


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    In Vitro

    In vitro activity: 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.


    Kinase Assay: 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 Assay: Cell proliferation assay is determined by MTS methods. Briefly, cells (PC-9 (exon 19Del), H3255 (L858R) and H838 (wt) 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 VivoAZD3759 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.
    Animal modelMice bearing PC-9 (Exon19Del) tumors
    Formulation & DosageFormulated in 1% methylcellulose; 15 mg/kg; Oral gavage
    References

    J Med Chem. 2015 Oct 22;58(20):8200-15


    These protocols are for reference only. InvivoChem does not independently validate these methods.

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