AZD-9291 mesylate

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

一种有效的、选择性的、第三代不可逆突变型 EGFR 抑制剂，对 L858R-T790M/L858R/L861Q 的 IC50 分别为 1/12/5 nM。

A potent, selective, third-generation irreversible inhibitor of mutant EGFR with IC50s of 1/12/5 nM for L858R-T790M/L858R/L861Q respectively; weak activity against wt EGFR (IC50=184 nM); inhibits signaling pathways and cellular growth in both EGFRm(+) and EGFRm(+)/T790M(+) mutant cell lines in vitro; exhibits tumor regression in EGFR-mutant tumor xenograft and transgenic models; orally active.Lung Cancer Approved(In Vitro):Osimertinib (AZD-9291) 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 Osimertinib. Osimertinib (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. (In Vivo):The tumor-bearing mice are treated with Osimertinib (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 Osimertinib, while 5 of 5 mice treated with vehicle shows tumor growth. Osimertinib (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. Osimertinib (AZD-9291) also offers an additional degree of broader chemical and profile 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 per day). The excellent efficacy is also observed when Osimertinib (AZD-9291) is dosed at 5 mg/kg per day.

Cell Proliferation Assay Cell Line:PC-9, H3255, PC-9ER, and H1975 cellsConcentration:0.0001, 0.001, 0.01, 0.1, 1, 10 μMIncubation Time:72 hoursResult:Dramatically inhibited cell proliferation (IC50=41,26, 41, 31 nM, respectively)Cell Proliferation AssayCell Line:Ba/F3 cells (harboring a T790M mutation, exon 19del+T790M, or L858R+T790M) Concentration:0.0001, 0.001, 0.01, 0.1, 1, 10 μMIncubation Time:72 hoursResult:Inhibited cell proliferation (IC50 = 6, 7, 74 nM, respectively)Cell Proliferation AssayCell Line:Ba/F3 cells (harboring EGFR exon 20 insertion mutations)Concentration:0.0001, 0.001, 0.01, 0.1, 1, 10 μM Incubation Time:72 hours Result:Inhibited cell proliferation (IC50 = 16, 701, 230, 38 nM, respectively)Apoptosis Analysis Cell Line:Ba/F3 cells(harboring EGFR exon 19del+T790M or EGFR L858R+T790M) Concentration:0.1 μM Incubation Time:48 hours Result:Inducted apoptosis with the rate of 40.9% and 90% in EGFR T790M positive mutations cells respectively.

Animal Model:PC-9 (ex19del) and H1975 (L858R/T790M) tumor xenograft modelsDosage:0.1-10 mg/kg (PC-9 xenograft models); 0.5- 25 mg/kg (H1975 xenograft models) Administration:p.o.; daily for 14 day Result:Induced significant dose-dependent regression in both PC-9 (ex19del) and H1975 (L858R/T790M) tumor xenograft models.

Osimertinib mesylate | Mereletinib mesylate | AZD9291 mesylate | AZD 9291 mesylate

Angiogenesis

EGFR

EGFR(L858R)|EGFR(L858R/T790M)|EGFRL858R/T790M|EGFRL858R

Cancer

Lung Cancer

1421373-66-1

595.713

C29H37N7O5S

>98% (HPLC)

DMSO

CN1C=C(C2=CC=CC=C21)C3=NC(=NC=C3)NC4=C(C=C(C(=C4)NC(=O)C=C)N(C)CCN(C)C)OC.CS(=O)(=O)O

2-Propenamide, N-[2-[[2-(dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-, methanesulfonate (1:1)

(-20℃)

With Ice Pack

≥ 2 years