AZD3759 is a potent and oral active inhibitor of EGFR (IC50= 7.0-7.7 nM) with antineoplastic activity.
EGFR (epidermal growth factor receptor) is a cell-surface receptor tyrosine kinase. The receptor activation leads to dimerization and tyrosine autophosphorylation. It induces a cascade of downstream cellular responses such as modification in gene expression, cell proliferation and cytoskeletal rearrangement etc.
AZD3759 shows equally potent inhibitory effect on cell phosphorylation or proliferation in EGFR-activating mutant cell lines (PC-9 and H3255) in the range of 7.0?7.7nM. In cellular phosphorylation assays, AZD3759 also exhibits 9-fold inhibition selectivity in EGFR-activating
mutant cell lines over EGFR wild-type cell lines (H838). [1]
In brain metastasis mouse model, AZD3759 demonstrates prominent antitumor efficacy in a dose dependent manner (～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). In addition, at the doses of 7.5 and 15 mg/k, AZD3759 significantly decreases tumor area in the brain tissue collected from the same mouse model. [1]
Reference:
Zeng Q, Wang J, Cheng Z et al. Discovery and Evaluation of Clinical Candidate AZD3759, a Potent, Oral Active, Central Nervous System-Penetrant, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor. J Med Chem. 2015 Oct 22;58(20):8200-15
