AZD-9291 是一种第三代不可逆的 EGFR 酪氨酸激酶抑制剂，选择性作用于野生型 EGFR，在EGFR重组酶实验中，作用于L858R 和 L858R/T790M型EGFR，IC50 分别为 12 nM 和 1 nM 发布时间：2017-09-25 17:57| 点击次数：

AZD-9291 是一种第三代不可逆的 EGFR 酪氨酸激酶抑制剂，选择性作用于野生型 EGFR，在EGFR重组酶实验中，作用于L858R 和 L858R/T790M型EGFR，IC50 分别为 12 nM 和 1 nM  Description

AZD-9291 is a third generation irreversible EGFR tyrosine kinase inhibitor with selectivity against mutant versus wild-type forms of EGFR, shows an apparent IC50 of 12 nM against L858R and 1 nM against L858R/T790M in EGFR recombinant enzyme assay.

IC50  Target

IC50: 1 nM (EGFRL858R/T790M), 12 nM (EGFRL858R)[1]

In Vitro

AZD-9291 (AZD9291) shows similar potency to early generation tyrosine kinase inhibitor (TKIs) in inhibiting EGFR phosphorylation in EGFR cells harboring sensitising EGFR mutants including PC-9 (ex19del), H3255 (L858R) and H1650 (ex19del), with mean IC50 values ranging from 13 to 54 nM for AZD-9291. AZD-9291 also potently inhibits phosphorylation of EGFR in T790M mutant cell lines (H1975 (L858R/T790M), PC-9VanR (ex19del/T790M), with mean IC50 potency less than 15 nM[1].

In Vivo

The tumor-bearing mice are treated with AZD-9291 (5 mg/kg/day) for one to two weeks. Within days of treatment, 5 of 5 C/L858R mice displays nearly 80% reduction in tumor volume by magnetic resonance imaging MRI after therapy with AZD-9291, while 5 of 5 mice treated with vehicle shows tumor growth[1]. AZD-9291 demonstrates improved rat PK, reduced hERG affinity, and improved IGF1R margins relative to the previously described compounds, and so this compound is selected for further investigation. AZD-9291 also offers an additional degree of broader chemical and profile diversity when compared to the previously described lead compounds. Upon dosing AZD-9291 in three efficacy models, The comparable efficacy is observed at relatively low doses (10 mg/kg per day). The excellent efficacy is also observed when AZD-9291 is dosed at 5 mg/kg per day[2].

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