Zorifertinib

MCE 国际站：Zorifertinib

产品活性：Zorifertinib (AZD3759) 是一种有效的，具有口服活性的，可渗透中枢神经系统的 EGFR 抑制剂。作用于 EGFR^wt，EGFR^L858R 和 EGFR^{exon 19Del}，IC₅₀ 分别为 0.3，0.2 和 0.2 nM。Zorifertinib 诱导癌细胞凋亡 (Apoptosis)。Zorifertinib 具有抗肿瘤活性，可用于NSCLC、HCC 等肿瘤的研究。

研究领域：JAK/STAT Signaling | Protein Tyrosine Kinase/RTK | Apoptosis

作用靶点：EGFR | Apoptosis

In Vitro: 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).

In Vivo: 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.

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