奧斯替尼作用機制 - Medchemexpress - MCE中國

1、Product Data SheetOsimertinibCat. No.: HY-15772CAS No.: 1421373-65-0分式: CHNO分量: 499.61作靶點: EGFR作通路: JAK/STAT Signaling; Protein Tyrosine Kinase/RTK儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實驗 DMSO : 100 mg/mL (200.16 mM; Need ultrasonic)H2O : 0.1 mg/mL (insoluble)S

2、olventMass1 mg 5 mg 10 mgConcentration制備儲備液1 mM 2.0016 mL 10.0078 mL 20.0156 mL5 mM 0.4003 mL 2.0016 mL 4.0031 mL10 mM 0.2002 mL 1.0008 mL 2.0016 mL請根據(jù)產(chǎn)品在不同溶劑中的溶解度選擇合適的溶劑配制儲備液；旦配成溶液，請分裝保存，避免反復凍融造成的產(chǎn)品失效。儲備液的保存式和期限：-80C, 6 months; -20C, 1 month。-80C 儲存時，請在 6 個內(nèi)使，-20C 儲存時，請在 1 個內(nèi)使。體內(nèi)實驗請根據(jù)您的實驗動物和給藥式選擇適當

3、的溶解案。以下溶解案都請先按照 In Vitro 式配制澄清的儲備液，再依次添加助溶劑：為保證實驗結果的可靠性，澄 的儲備液可以根據(jù)儲存條件，適當保存；體內(nèi)實驗的作液，建議您現(xiàn)現(xiàn)配，當天使； 以下溶劑前顯的百分 指該溶劑在您配制終溶液中的體積占；如在配制過程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過加熱和/或超聲的式助溶1. 請依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (5.00 mM); Clear solution此案可獲得 2.5 mg/mL (5.00 mM，飽和度未知) 的澄清溶液。以 1

4、mL 作液為例，取 100 L 25.0 mg/mL 的澄 DMSO 儲備液加到 400 L PEG300 中，混合均勻；向上述體系中加50 L Tween-80，混合均勻；然后繼續(xù)加 450 L 理鹽定容 1 mL。2. 請依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (5.00 mM); Clear solutionPage 1 of 2 www.MedChemE此案可獲得 2.5 mg/mL (5.00 mM，飽和度未知) 的澄 溶液，此案不適于實驗周 期在半個以上的實驗。以 1 mL 作液為例，取 100 L 25.0 mg/

5、mL 的澄 DMSO 儲備液加到 900 L 油中，混合均勻。BIOLOGICAL ACTIVITY物活性 Osimertinib (AZD-9291) 別為12 和 1 nM。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IC & Target EGFRL858R EGFRL858R/T790M12 nM (IC50, Enzyme 1 nM (IC50, Enzyme assays)assays)體外研究 Osimertinib (AZD-9291) shows similar potency to early gen

6、eration tyrosine kinase inhibitor (TKIs) in inhibiting EGFRphosphorylation in EGFR cells harboring sensitising EGFR mutants including PC-9 (ex19del), H3255 (L858R) andH1650 (ex19del), with mean IC50 values ranging from 13 to 54 nM for AZD-9291. Osimertinib (AZD-9291) alsopotently inhibits phosphoryl

7、ation of EGFR in T790M mutant cell lines (H1975 (L858R/T790M), PC-9VanR(ex19del/T790M), with mean IC50 potency less than 15 nM1.體內(nèi)研究 The tumor-bearing mice are treated with Osimertinib (AZD-9291) (5 mg/kg/day) for one to two weeks. Within days oftreatment, 5 of 5 C/L858R mice displays nearly 80% red

8、uction in tumor volume by magnetic resonance imaging MRIafter therapy with Osimertinib (AZD-9291), while 5 of 5 mice treated with vehicle shows tumor growth1. Osimertinib(AZD-9291) demonstrates improved rat PK, reduced hERG affinity, and improved IGF1R margins relative to thepreviously described com

9、pounds, and so this compound is selected for further investigation. Osimertinib (AZD-9291)also offers an additional degree of broader chemical and profile diversity when compared to the previously describedlead compounds. Upon dosing Osimertinib (AZD-9291) in three efficacy models, The comparable ef

10、ficacy is observedat relatively low doses (10 mg/kg per day). The excellent efficacy is also observed when Osimertinib (AZD-9291) isdosed at 5 mg/kg per day2.PROTOCOLCell Assay 1 PC-9 cells are seeded into T75 flasks (5105 cells/flask) in RPMI growth media and incubated at 37C, 5% CO2. Thefollowing

11、day the media is replaced with media supplemented with a concentration of EGFR inhibitor equal to the EC50 concentration predetermined in PC-9 cells. Media changes are carried out every 2-3 days and resistant clonesallowed to grow to 80% confluency prior to the cells being trypsinised and reseeded a

12、t the original seeding densityin media containing twice the concentration of EGFR inhibitor. Dose escalations are continued until a finalconcentration of 1.5 M ZD1839, 1.5 M BIBW 2992, 1.5 M WZ4002 or 160 nM Osimertinib (AZD-9291) areachieved1.MCE has not independently confirmed the accuracy of thes

13、e methods. They are for reference only.Animal Mice1Administration 12 The EGFRL858R and EGFRL858R+T790M mice (male and female) are used. Osimertinib (AZD-9291) is suspended in 1%Polysorbate 80 and administered via oral gavage once daily at the doses of 7.5 mg/kg and 5 mg/kg, respectively.Mice are ima

14、ged weekly at the Vanderbilt University Institute of Imaging Science. For immunoblot analysis, mice aretreated for eight hours with drug as described before dissection and flash freezing of the lungs. Lungs are pulverizedin liquid nitrogen before lysis.Rats2The male RccHan:WIST rats (10-week-old) ar

15、e received a single oral dose of Osimertinib (AZD-9291) (200 mg/kg).Page 2 of 3 www.MedChemEBlood 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 Cancer Discov. 2019 Jul;9(7):926-943

16、. Cancer Cell. 2020 Jan 13;37(1):104-122.e12. Cell Chem Biol. 2018 Aug 16;25(8):996-1005.e4. Cancers (Basel). 2019 Oct 14;11(10). pii: E1550. Cancers (Basel). 2019 Jul 5;11(7). pii: E947.See more customer validations on HYPERLINK www.MedChemE www.MedChemEREFERENCES1. Cross DA, et al. AZD9291, an irr

17、eversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014Sep;4(9):1046-61.2. Finlay MR, et al. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistancemutations that spares the wildtype form of the receptor. J Me