AZD-9291 (Mesylate)
Synonyms:AZD-9291 (Mesylate);N-[2-[[2-(Dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide methanesulfonate (1:1);AZD-9291 mesylate N-[2-[[2-(Dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide methanesulfonate (1:1)
CAS:1421373-66-1
MF:C28H33N7O2.CH4O3S
AZD-9291 is a potent and selective mutated forms EGFR inhibitor(Exon 19 deletion EGFR IC50=12.92 nM, L858R/T790M EGFR IC50= 11.44 nM, wild type EGFR IC50= 493.8 nM).
IC50 value: 12.92 nM(Exon 19 deletion EGFR); 11.44 nM(L858R/T790M EGFR) [1]
Target: L858R/T790M EGFR; Exon 19 deletion EGFR
First-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provide significant clinical benefit in patients with advanced EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, usually due to the acquisition of the resistance mutation. AZD9291 is a oral, potent, and selective third generation irreversible inhibitor of both EGFRm sensitizing and T790M resistance mutants which spares wild-type EGFR.
In vitro: AZD9291 potently inhibits signaling pathways and cellular growth in both EGFRm and EGFRm/T790M mutant cell lines, with lower activity against WT EGFR cell lines. AZD9291 showed an apparent IC50 of 12 nmol/L against L858R and 1 nmol/L against L858R/T790M EGFRm.
In vivo: AZD9291 demonstrates good bioavailability, is widely distributed in tissues, and has moderate clearance resulting in a half-life of around 3 hours after oral dosing in the mouse . Once-daily dosing of AZD9291 induced significant dose-dependent regression in both PC-9 (ex19del) and H1975 (L858R/T790M) tumor xenograft models. The tumor shrinkage was observed at doses low to 2.5 mg kg-1 day-1 in both models.
Clinical trial: The mesylate salt of AZD9291 is currently in a first-in-human phase I dose-escalation clinical trial (AURA; NCT01802632; AstraZeneca) in patients with advanced EGFRm NSCLC who had disease progression following treatment with any EGFR TKI (including gefitinib or erlotinib). AZD9291 is showing promising responses in this phase I trial even at the first-dose level.
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