Osimertinib mesylate 是一种不可逆的突变选择性 EGFR 抑制剂，对EGFRL858R和EGFRL858R/T790M的IC50值分别为 12 和 1 nM。

Osimertinib (AZD-9291) is an irreversible and mutant selective EGFR inhibitor (IC50s: 12/1 nM for EGFR(L858R) and EGFR(L858R/T790M)).

In EGFR recombinant enzyme assays, osimertinib (AZD9291) showed an apparent IC50 of 12 nM against L858R and 1 nM against L858R/T790M. The drug exhibited nearly 200 times greater potency against L858R/T790M than wild-type EGFR. AZD9291 showed similar potency to early generation TKIs in inhibiting EGFR phosphorylation in EGFR cells harboring sensitizing EGFR mutants including PC-9 (ex19del), H3255 (L858R) and H1650 (ex19del), with mean IC50 values ranging from 13 to 54 nM for AZD9291. AZD9291 also potently inhibited phosphorylation of EGFR in T790M mutant cell lines (H1975 (L858R/T790M), PC-9VanR (ex19del/T790M), with mean IC50 potency less than 15 nM [1]. In the presence of osimertinib, the intracellular accumulations of DOX and Rho 123 significantly increased in KBv200 and S1-MI-80 cells while not in the sensitive KB and S1 cells. Osimertinib increased the intracellular accumulation of Hoechst 33342 in resistant H460/MX20 and HEK293/ABCG2 cells rather than in sensitive H460 and HEK293/Vector cells. Furthermore, the increased effect produced by osimertinib at 0.2 μmol/L or 0.4 μmol/L was comparable with that of FTC at 2.5 μmol/L or VRP at 10 μmol/L [2].

Once daily dosing of AZD9291 induced significant dose-dependent regression in both PC-9 (ex19del) and H1975 (L858R/T790M) tumor xenograft models, with tumor shrinkage observed at doses as low as 2.5mg/kg/day in both models after 14 days. Similar tumor shrinkage was seen after administration of 5 mg/kg/day AZD9291 in H3255 (L858R) and PC-9VanR (ex19 del/ T790M) xenografts after 14 days [1]. The combination of osimertinib and paclitaxel produced a greater inhibitory effect on xenograft growth compared with animals treated with only saline, paclitaxel, or osimertinib, and the inhibition rate was 52.7% [2]. AZD9291 demonstrated improved rat PK, reduced hERG affinity, and improved IGF1R margins. AZD9291 also offered an additional degree of broader chemical and profile diversity. Upon dosing AZD9291 in our three efficacy models, comparable efficacy was observed at relatively low doses (10 mg/kg/day). Excellent efficacy was also observed when 8 was dosed at 5 mg/kg/day [3].

Kinase assays were performed as per the EMD Millipore profiling service protocol using peptide or protein substrates in a filter-binding radioactive ATP transferase assay for protein [1].

PC-9 cells were seeded into T75 flasks (5 × 10^5 cells/flask) in RPMI growth media and incubated at 37°C, 5% CO2. The following day the media was replaced with media supplemented with a concentration of EGFR inhibitor equal to the EC50 concentration predetermined in PC-9 cells. Media changes were 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 were continued until a final concentration of 1.5μM gefitinib, 1.5μM afatinib, 1.5μM WZ4002 or 160nM AZD9291 were achieved [1].

The generation of EGFRL858R and EGFRL858R+T790M mice (male and female) was previously described Doxycycline was administered by feeding mice (aprox 3 week old) with doxycycline-impregnated food pellets (625 ppm) and treated for about 3 months during which time tumors developed. Afatinib and AZD9291 were 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 were imaged weekly at the Vanderbilt University Institute of Imaging Science. For immunoblot analysis, mice were treated for eight hours with drug as described before dissection and flash freezing of the lungs. Lungs were pulverized in liquid nitrogen before lysis as described above [1].

1421373-66-1

C29H37N7O5S

595.72

甲磺酸奥希替尼;Mereletinib mesylate;AZD-9291 mesylate;奥希替尼甲磺酸盐

DMSO:9 mg/mL(15.1 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years