AZD-9291 is a third-generation EGFR inhibitor, showed promise in preclinical studies and provides hope for patients with advanced lung cancers that have become resistant to existing EGFR inhibitors.12.92 nM(Exon 19 deletion EGFR); 11.44 nM(L858R/T790M EGFR）
|Source||Mol Pharm (2016). Figure 2.AZD-9291|
|Cell Lines||cancer cell lines|
|Concentrations||0.1 - 1 μM|
|Incubation Time||72 h|
|Results||Cells were maintained in the absence or presence of increasing concentrations (0.1 - 1 μM) of osimertinib for 72 h, harvested and processed for immunoblotting as described in Materials and methods.|
|Source||Mol Pharm (2016). Figure 1.AZD-9291|
|Cell Lines||MDR19-HEK293 cells|
|Incubation Time||24 h|
|Results||Osimertinib (10 μM) significantly increased the accumulation of fluorescent calcein, an established substrate of ABCB145 in ABCB1-overexpressing KB-V-1 cells and ABCB1-transfected MDR19-HEK293 cells to the same extent as tariquidar, a known inhibitor of ABCB1|
|Cell lines||PC-9 cells|
|Preparation method||Media changes are carried out every 2-3 days and resistant clones allowed to grow to 80% confluency prior to the cells being trypsinised and reseeded at the original seeding density in media containing twice the concentration of EGFR inhibitor. Dose escalations are continued until a final concentration of 1.5 μM Gefitinib, 1.5 μM Afatinib, 1.5 μM WZ4002 or 160 nM AZD-9291 are achieved.|
|Incubation time||48 h|
|Formulation||1% Polysorbate 80|
|Dosages||7.5 mg/kg and 5 mg/kg|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||10 mM in DMSO|
Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor.
Finlay MR, et al. J Med Chem. 2014 Oct 23;57(20):8249-67. PMID: 25271963.
AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.
Cross DA, et al. Cancer Discov. 2014 Sep;4(9):1046-61. PMID: 24893891.
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