AZD-9291 mesylate

SKU: orb1226316

Description

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.\n(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.

Key Properties

• CAS Number: 1421373-66-1
• MW: 595.713
• Purity: >98% (HPLC)
• Formula: C₂₉H₃₇N₇O₅S
• SMILES: 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
• Target: EGFR
• Solubility: DMSO

Bioactivity

• In Vivo:
  Animal model: PC-9 (ex19del) and H1975 (L858R/T790M) tumor xenograft models. Dosage: 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.
• In Vitro:
  Cell Proliferation Assay Cell line: PC-9, H3255, PC-9ER, and H1975 cells. Concentration: 0.0001, 0.001, 0.01, 0.1, 1, 10 μM Incubation time: 72 hours. Result: Dramatically inhibited cell proliferation (IC50 = 41, 26, 41, 31 nM, respectively)Cell Proliferation Assay Cell 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 μM Incubation time: 72 hours. Result: Inhibited cell proliferation (IC50 = 6, 7, 74 nM, respectively)Cell Proliferation Assay Cell 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.

Storage & Handling

• Storage: Storage temperature: -20°C. Stability: ≥ 2 years
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

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

Quick Database Links

Gene Symbol

EGFR