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Osimertinib

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Chemical Structure| 1421373-65-0 同义名 : 奥希替尼 (AZD9291) ;AZD-9291;Mereletinib
CAS号 : 1421373-65-0
货号 : A157172
分子式 : C28H33N7O2
纯度 : 99%
分子量 : 499.607
MDL号 : MFCD27988062
存储条件：

粉末 Keep in dark place,Inert atmosphere,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 105 mg/mL(210.17 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

5%DMSO+40%PEG300+5%Tween80+50%water 7.5 mg/mL

生物活性
靶点

  • EGFR/ErbB1

    WT EGFR, IC50:12.92 nM

    L858R/T790M EGFR, IC50:11.44 nM
描述 EGFR (epidermal growth factor receptor) family consists of four members that belong to the ErbB lineage of proteins (ErbB1 - 4) with an external domain that binds activating ligands, such as EGF. EGFR T790M mutation is the most common mechanism of drug resistance. Osimertinib is an irreversible EGFR inhibitor which more potent to mutant-selective EGFR with IC50 values of 12.92 nM, 11.44 nM and 493.8 nM for Exon 19 deletion EGFR, L858R/T790M EGFR and WT EGFR, with a 200-fold selectivity for T790M/L858R over wild type EGFR, in LoVo cells, respectively[1]. Osimertinib potently inhibits EGFR phosphorylation in EGFRm+ (e.g. PC9; <25nM) and EGFRm+/T790M (e.g. H1975; <25nM) cell lines in vitro, whilst demonstrating much less activity against wild-type EGFR lines (e.g. LoVo; >500nM). Consistent with that, AZD9291 showed significantly more potent inhibition of proliferation in mutant EGFR cell lines compared to wild-type in vitro. Oral administration of Osimertinib once daily at dose of 5mg/kg caused profound regression of tumors across EGFRm+ (PC9; 178% growth inhibition) and EGFRm+/T790M (H1975; 119% growth inhibition) tumor models in vivo, after 14 days dosing, and this was associated with profound inhibition of EGFR phosphorylation and key downstream signaling pathways such as AKT and ERK. Chronic long-term treatment of PC9 and H1975 xenograft tumors with Osimertinib led to a complete and sustained macroscopic response, with no visible tumors after 40 days dosing, and being maintained beyond 100 days[2].
作用机制 Osimertinib may bind to T790M EGFR kinase in the ATP-binding domain (such as T790M and C797S) [3].
细胞研究
细胞系 浓度 检测类型 检测时间 活动说明 数据源
PC9 0-10 μM Function Assay 72 h inhibits WT EGFR at low concentrations 25948633
PC9 GR4 0-10 μM Growth Inhibition Assay 72 h inhibits cell growth dose dependently 25948633
PC9 GR4 0-10 μM Function Assay 72 h inhibits EGFR phosphorylation and downstream signaling  25948633
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.00mL

0.40mL

0.20mL

10.01mL

2.00mL

1.00mL

20.02mL

4.00mL

2.00mL
参考文献

[1]2 - (2, 4, 5 - substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer

[2]AZD9291: an irreversible, potent and selective third generation tyrosine kinase inhibitor (TKI) targeting EGFR activating (EGFRm+) and resistance (T790M) mutations in advanced lung adenocarcinoma.

[3]Yosaatmadja Y, Silva S, et al. Binding mode of the breakthrough inhibitor AZD9291 to epidermal growth factor receptor revealed. J Struct Biol. 2015 Dec;192(3):539-544.

[4]THE CDK4/6 INHIBITOR, G1T38, ENHANCES RESPONSE TO TARGETED THERAPIES IN PRECLINICAL MODELS OF NON-SMALL CELL LUNG CANCER

[5]Floc'h N, Martin MJ, et al. Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions. Mol Cancer Ther. 2018 May;17(5):885-896.

[6]Pharmacokinetics of osimertinib