Zorifertinib  (Synonyms: AZD3759)

Zorifertinib (AZD3759) is a potent, orally active, BBB-penetrant, EGFR inhibitor. At K_m ATP concentrations, the IC₅₀s are 0.3, 0.2, and 0.2 nM for EGFR^wt, EGFR^L858R, and EGFR^{exon 19Del}, respectively. Zorifertinib induces cancer cell apoptosis. Zorifertinib has antitumor activity, and can be used for NSCLC, HCC etc. research^[1].

At 2 mM of ATP concentrations, the IC₅₀s are 102, 7.6, and 2.4 nM for EGFR^wt, EGFR^L858R, and EGFR^{exon 19Del}, respectively. Zorifertinib (AZD3759) also inhibits pEGFR in H838^wt, H3255^L858R, and PC-9^{exon 19Del} with IC₅₀ of 64.5, 7.2, and 7.4 nM, respectively. In cellular phosphorylation studies, Zorifertinib also demonstrates 9-fold inhibition selectivity in EGFR-activating mutant cell lines over EGFR wild-type cell lines (H838 cell line)^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Following oral dosing in rats at 2 mg/kg, absorption of Zorifertinib (AZD3759) is rapid with blood C_max of 0.58 μM achieved at 1.0 h. Subsequently, blood concentrations of Zorifertinib decline monoexponentially with a mean elimination half-life of 4.3 h, which is close to the same parameter obtained from intravenous dosing of 4.1 h. The bioavailability following an oral dose in rats is 91%. Blood pharmacokinetic parameters of Zorifertinib in male dogs are determined following both a single dose intravenous infusion and oral administration. Following the IV dose in dogs, Zorifertinib blood clearance is determined as 14 mL/min per kg, and the volume of distribution is 6.4 L/kg. Its elimination half-life is 6.2 h. Absorption of Zorifertinib is rapid with blood C_max (698 nM) occurring between 0.5 and 1.5 h. The oral bioavailability of Zorifertinib is excellent at 90%. Zorifertinib demonstrated significant dose-dependent antitumor efficacy (78% tumor growth inhibition at 7.5 mg/kg qd and tumor regression at 15 mg/kg qd, respectively, 4 weeks after treatment) with <20% body weight loss, whereas CP-358774 has a limited effect in this model. At the end of the study, brain tissues are collected for histological assessment. Significantly decreased tumor area is observed by Zorifertinib treatment at the doses of 7.5 and 15 mg/kg. In addition, modulation of pEGFR is detected by a single dose of Zorifertinib at 15 mg/kg 1h after dosing, which confirmed target engagement by Zorifertinib^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

459.90

C₂₂H₂₃ClFN₅O₃

1626387-80-1

Solid

White to off-white

ClC1=CC=CC(NC2=NC=NC3=CC(OC)=C(OC(N4[C@H](C)CN(C)CC4)=O)C=C23)=C1F

Room temperature in continental US; may vary elsewhere.

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 2 years; -20°C, 1 year. When stored at -80°C, please use it within 2 years. When stored at -20°C, please use it within 1 year.

• [1]. Zeng Q, et al. Discovery and Evaluation of Clinical Candidate AZD3759, a Potent, Oral Active, Central Nervous System-Penetrant, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor. J Med Chem. 2015 Oct 22;58(20):8200-15.  [Content Brief]

  [2]. Chao D, et al. AZD3759 induces apoptosis in hepatoma cells by activating a p53-SMAD4 positive feedback loop. Biochem Biophys Res Commun. 2019 Feb 5;509(2):535-540.  [Content Brief]