Osimertinib

Osimertinib (AZD9291) is a covalent, orally active, irreversible, and mutant-selective EGFR inhibitor with an apparent IC₅₀ of 12 nM against L858R and 1 nM against L858R/T790M, respectively. Osimertinib overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer^[1]. IC50 & Target: IC50: 1 nM (EGFR^L858R/T790M), 12 nM (EGFR^L858R)^[1] In Vitro: Osimertinib (AZD9291) (0-10 μM; 72 hours) dramatically inhibits cell proliferation with IC₅₀s of 41, 26, 41, and 31 nM, respectively^[2].
Osimertinib (0-10 μM; 72 hours) inhibits cell proliferation (Ba/F3 cells harboring a T790M mutation, exon 19del+T790M, or L858R+T790M) with IC₅₀s of 6, 7, and 74 nM, respectively^[2].
Osimertinib (0-10 μM; 72 hours) inhibits Ba/F3 cells harboring EGFR exon 20 insertion mutations (IC₅₀ ranging from 16 to 701 nM for A763_Y764insFQEA (FQEA), Y764_V765insHH (HH), A767_V769dupASV (ASV), and D770_N771insNPG (NPG) cells)^[2].
Osimertinib shows high levels of phenotype potency in both sensitizing-mutant (mean IC₅₀ of 8 nM in PC-9) and T790M (mean IC₅₀s of 11 and 40 nM in H1975 and PC-9VanR respectively) EGFR cell lines. Osimertinib has much less activity towards wild-type EGFR (mean IC₅₀s of 650 and 461 nM in Calu3 and H2073 respectively)^[1].
Osimertinib (0.1 μM; 48 hours) induces apoptosis in Ba/F3 cells (apoptosis rates of 40.9% and 90% in EGFR exon 19del+T790M, EGFR L858R+T790M respectively) ^[2]. In Vivo: Osimertinib (0.1-25 mg/kg; p.o.; daily for 14 days) induces significant dose-dependent regression in both PC-9 (ex19del) and H1975 (L858R/T790M) tumor xenograft models^[1].