Discovery and Evaluation of Clinical Candidate AZD3759, a Potent, Oral Active, Central Nervous System-Penetrant, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

Recent
reports suggest that an increasing number of patients with
lung cancer, especially those with activating mutations of the epidermal
growth factor receptor (EGFR), also present with brain metastases
and leptomeningeal metastases. These patients have poor prognosis
as there are no approved drugs for these indications. Available agents
have poor efficacy for these patients even at well above their standard
dose. Herein, we report the discovery of (4-[(3-chloro-2-fluorophenyl)­amino]-7-methoxyquinazolin-6-yl
(2R)-2,4-dimethylpiperazine-1-carboxylate 1m (AZD3759), an investigational drug currently in Phase 1 clinical
trial, which has excellent central nervous system penetration and
which induces profound regression of brain metastases in a mouse model.