Zorifertinib (AZD3759)

Catalog No.S7971 Batch:S797102

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Technical Data

Formula

C22H23ClFN5O3
Molecular Weight 459.90 CAS No. 1626387-80-1
Solubility (25°C)* In vitro DMSO 91 mg/mL (197.86 mM)
Ethanol 20 mg/mL (43.48 mM)
Water Insoluble
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.)

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Biological Activity

Description 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.
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 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]
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]

Protocol (from reference)

Kinase Assay:[1]
  • 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.
Cell Assay:[1]
  • Cell lines

    PC-9 (exon 19Del), H3255 (L858R) and H838 (wt) cells

  • Concentrations

    ~30 mM

  • Incubation Time

    72 h

  • Method

    Zorifertinib (AZD3759) cell proliferation 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 this compound 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.
Animal Study:[1]
  • Animal Models

    Mice bearing PC-9 (Exon19Del) tumors

  • Dosages

    ~15 mg/kg

  • Administration

    p.o.

References

  • https://pubmed.ncbi.nlm.nih.gov/26313252/

Selleck's Zorifertinib (AZD3759) Has Been Cited by 6 Publications

A Novel Network Pharmacology Strategy Based on the Universal Effectiveness-Common Mechanism of Medical Herbs Uncovers Therapeutic Targets in Traumatic Brain Injury [ Drug Des Devel Ther, 2024, 18:1175-1188] PubMed: 38645986
Aurora kinase blockade drives de novo addiction of cervical squamous cell carcinoma to druggable EGFR signalling [ Oncogene, 2022, 10.1038/s41388-022-02256-3] PubMed: 35250028
Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology [ Acta Neuropathol, 2020, 10.1007/s00401-020-02226-7] PubMed: 33009951
YH25448, an Irreversible EGFR-TKI with Potent Intracranial Activity in EGFR Mutant Non-Small Cell Lung Cancer [ Clin Cancer Res, 2019, 25(8):2575-2587] PubMed: 30670498
IP1867B suppresses the insulin-like growth factor 1 receptor (IGF1R) ablating epidermal growth factor receptor inhibitor resistance in adult high grade gliomas [ Cancer Lett, 2019, 458:29-38] PubMed: 31129148
Brain distribution of a panel of EGFR inhibitors using cassette-dosing in wild-type and Abcb1/Abcg2 deficient mice [Kim M Drug Metab Dispos, 2019, 10.1124/dmd.118.084210] PubMed: 30705084

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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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