Osimertinib-AZD-9291-DataSheet-生命科學(xué)試劑-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEOsimertinibCat. No.: HY-15772CAS No.: 1421373-65-0Synonyms: AZD-9291; Mereletinib分式: CHNO分量: 499.61作靶點(diǎn): EGFR作通路: JAK/STAT Signaling; Protein Tyrosine Kinase/RTK儲(chǔ)存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 mon

2、th溶解性數(shù)據(jù)體外實(shí)驗(yàn) DMSO : 100 mg/mL (200.16 mM; Need ultrasonic)H2O : 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (5.00 mM); Clear solution2. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (5.00 mM); Clear solution1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEBIOLOGICAL ACTIVITY物活性 Osi

3、mertinib (AZD-9291)種不可逆和突變的選擇性的 EGFR 抑制劑，抑制EGFRL858R 和EGFRL858R/T790M 的 IC50 分別為12 和 1 nM。IC50 & Target EGFRL858R EGFRL858R/T790M12 nM (IC50, Enzyme assays) 1 nM (IC50, Enzyme assays)體外研究 Osimertinib (AZD-9291) shows similar potency to early generation tyrosine kinase inhibitor (TKIs) in inhibitingE

4、GFR 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. Osimertinib(AZD-9291) also potently inhibits phosphorylation of EGFR in T790M mutant cell lines (H1975(L858R/T

5、790M), PC-9VanR (ex19del/T790M), with mean IC50 potency less than 15 nM 1.體內(nèi)研究 The tumor-bearing mice are treated with Osimertinib (AZD-9291) (5 mg/kg/day) for one to two weeks. Withindays of treatment, 5 of 5 C/L858R mice displays nearly 80% reduction in tumor volume by magneticresonance imaging MR

6、I after therapy with Osimertinib (AZD-9291), while 5 of 5 mice treated with vehicleshows tumor growth 1. Osimertinib (AZD-9291) demonstrates improved rat PK, reduced hERG affinity, andimproved IGF1R margins relative to the previously described compounds, and so this compound is selectedfor further i

7、nvestigation. Osimertinib (AZD-9291) also offers an additional degree of broader chemical andprofile diversity when compared to the previously described lead compounds. Upon dosing Osimertinib (AZD-9291) in three efficacy models, The comparable efficacy is observed at relatively low doses (10 mg/kg

8、perday). The excellent efficacy is also observed when Osimertinib (AZD-9291) is dosed at 5 mg/kg per day 2.PROTOCOLCell Assay 1 PC-9 cells are seeded into T75 flasks (5105 cells/flask) in RPMI growth media and incubated at 37C, 5%CO2. The following day the media is replaced with media supplemented w

9、ith a concentration of EGFRinhibitor equal to the EC50 concentration predetermined in PC-9 cells. Media changes are carried out every2-3 days and resistant clones allowed to grow to 80% confluency prior to the cells being trypsinised andreseeded at the original seeding density in media containing tw

10、ice the concentration of EGFR inhibitor. Doseescalations are continued until a final concentration of 1.5 M ZD1839, 1.5 M BIBW 2992, 1.5 M WZ4002or 160 nM Osimertinib (AZD-9291) are achieved 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice

11、1Administration 12 The EGFRL858R and EGFRL858R+T790M mice (male and female) are used. Osimertinib (AZD-9291) issuspended in 1% Polysorbate 80 and administered via oral gavage once daily at the doses of 7.5 mg/kg and5 mg/kg, respectively. Mice are imaged weekly at the Vanderbilt University Institute

12、of Imaging Science. Forimmunoblot analysis, mice are treated for eight hours with drug as described before dissection and flashfreezing of the lungs. Lungs are pulverized in liquid nitrogen before lysis.Rats 22/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEThe male RccHan:WIST rats (10-week-old) ar

13、e received a single oral dose of Osimertinib (AZD-9291) (200mg/kg). Blood glucose levels are measured using an Accuchek Active meter.MCE has not independently confirmed the accuracy of these methods. They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻(xiàn) Cancer Discov. 2019 Jul;9(7):926-943. Cell Chem Biol. 2018 A

14、ug 16;25(8):996-1005.e4. Cancers. 2019 Jul. J Med Chem. 2017 Apr 13;60(7):2944-2962. Cell Death Dis. 2019 Aug; 10(8): 615.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Cross DA, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. CancerDiscov. 2014 Sep;4(9):1046-61.2. Finlay MR, et al. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistancemutations thatspares the wild type form of the receptor. J Med Chem. 2014