Biological Activity
AZD3759 is a potent, oral active, central nervous system-penetrant, EGFR inhibitor. At Km ATP concentrations, the IC50s are 0.3, 0.2, and 0.2 nM for EGFRwt, EGFRL858R, and EGFRexon 19Del, respectively.
In Vitro
At 2 mM of ATP concentrations, the IC50s are 102, 7.6, and 2.4 nM for EGFRwt, EGFRL858R, and EGFRexon 19Del, respectively. AZD3759 also inhibits pEGFR in H838wt, H3255L858R, and PC-9exon 19Del with IC50 of 64.5, 7.2, and 7.4 nM, respectively. In cellular phosphorylation studies, AZD3759 also demonstrates 9-fold inhibition selectivity in EGFR-activating mutant cell lines over EGFR wild-type cell lines (H838 cell line)[1].
In Vivo
Following oral dosing in rats at 2 mg/kg, absorption of AZD3759 is rapid with blood Cmax of 0.58 μM achieved at 1.0 h. Subsequently, blood concentrations of AZD3759 decline monoexponentially with a mean elimination half-life of 4.3 h, which is close to the same parameter obtained from intravenous dosing of 4.1 h. The bioavailability following an oral dose in rats is 91%. Blood pharmacokinetic parameters of AZD3759 in male dogs are determined following both a single dose intravenous infusion and oral administration. Following the IV dose in dogs, AZD3759 blood clearance is determined as 14 mL/min per kg, and the volume of distribution is 6.4 L/kg. Its elimination half-life is 6.2 h. Absorption of AZD3759 is rapid with blood Cmax (698 nM) occurring between 0.5 and 1.5 h. The oral bioavailability of AZD3759 is excellent at 90%. AZD3759 demonstrated significant dose-dependent antitumor efficacy (78% tumor growth inhibition at 7.5 mg/kg qd and tumor regression at 15 mg/kg qd, respectively, 4 weeks after treatment) with <20% body weight loss, whereas erlotinib had a limited effect in this model. At the end of the study, brain tissues are collected for histological assessment. Significantly decreased tumor area is observed by AZD3759 treatment at the doses of 7.5 and 15 mg/kg. In addition, modulation of pEGFR is detected by a single dose of AZD3759 at 15 mg/kg 1h after dosing, which confirmed target engagement by AZD3759[1].
References & source
Published experimental findings depend on the model and assay conditions. They do not guarantee equivalent performance in every application. For laboratory research use only.
